ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANESTHETIC AND LIFE SUPPORT DRUGS**
>
> **ADVISORY COMMITTEE**
>
> Wednesday, September 10, 2003
>
> 8:00 a.m.
>
> Holiday Inn Bethesda
>
> Bethesda, Maryland
>
> PARTICIPANTS
>
> Nathaniel P. Katz, M.D., Chair
>
> Johanna Clifford M.S., RN, BSN, Executive Secretary
>
> MEMBERS:
>
> Solomon Aronson, M.D.
>
> Madelyn Kahana, M.D.
>
> Steven L. Shafer, M.D.
>
> Mary Beth Bobek, Pharm.D., Consumer Representative
>
> Vera Bril, M.D.
>
> Bhupinder Saini, M.D.
>
> Carol Rose, M.D.
>
> VOTING CONSULTANTS:
>
> Louis E. Baxter, Sr., M.D., Drug Abuse Subcommittee
>
> Domenic Ciraulo, M.D., Drug Abuse Subcommittee
>
> Stephanie Crawford, Ph.D., M.S., Drug Safety and Risk Management
> Advisory Committee
>
> John Cush, M.D., Arthritis Advisory Committee
>
> Robert Dworkin, Ph.D.
>
> Jacqueline Gardner, Ph.D., M.P.H., Drug Safety and Risk Management
> Advisory Committee
>
> Jane Maxwell, Ph.D., Drug Abuse Subcommittee
>
> Gregory Skipper, M.D., F.A.S.M., Drug Abuse Subcommittee
>
> Brian Strom, M.D., M.P.H., Drug Safety and Risk Management Advisory
> Committee
>
> David J. Wlody, M.D.
>
> James Gillett, Ph.D., Voting Patient Representative:
>
> Charles McLeskey, M.D., Industry Representative
>
> NON-VOTING PARTICIPANTS:
>
> Mary Jeanne Kreek, M.D.
>
> Laura Nagel
>
> Terrance Woodworth, M.D.
>
> Judy Ball, Ph.D.,, M.P.H.
>
> Joe Gfroerer
>
> Arthur G. Lipman, Pharm.D.
>
> Elizabeth Willis, Ed.D.
>
> Deborah Trunzo
>
> FDA STAFF:
>
> Robert J. Meyer, M.D.
>
> John Jenkins, M.D.
>
> Bob Rappaport, M.D.
>
> Sharon Hertz, M.D.
>
> Deborah B. Leiderman, M.D., M.A.
>
> Anne Trontell, M.D., M.P.H.
>
> [C O N T E N T S]{.underline}
>
> Call to Order and Opening Remarks,
>
> Nathaniel Katz, M.D. 4
>
> Conflict of Interest
>
> Johanna Clifford, M.S., RN, BSN 5
>
> Committee Discussion 7
>
> Sponsor Presentation:
>
> Palladone Capsules for the Management of Persistent
>
> Moderate to Severe Pain in Opioid-Tolerant
>
> Patients
>
> Palladone Risk Management Program,
>
> J. David Haddox, D.D.S., M.D. 37
>
> RADARS Surveillance System,
>
> Sidney H. Schnoll, M.D., Ph.D. 65
>
> Prescription Drug Abuse, Herbert D. Kleber, M.D. 80
>
> Questions from the Committee 88
>
> Abuse Liability of Hydromorphone Extended-Release
>
> Capsules, Silvia Calderon, Ph.D. 125
>
> Long-Acting Opioids: Challenges in Pharmacotherapy,
>
> Mary Jeanne Kreek, M.D. 143
>
> FDA Presentation, Sharon Hertz, M.D. 179
>
> Open Public Hearing:
>
> Tom Stinson, M.D. 190
>
> Art Van Zee, M.D. 192
>
> Committee Discussion 201
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Opening Remarks**
>
> DR. KATZ: Good morning. Once again, this is a meeting of the
> Anesthetic and Life-Support Drugs Advisory Committee. My name is
> Nathaniel Katz.
>
> I wanted to make brief opening comments. First of all, in terms of
> committee discussion and in terms of speaker presentations, the ground
> rules for today will be the same as yesterday. If anybody around the
> table feels that they want to direct any questions to anybody just
> raise your hand and we will recognize you, and those would go through
> me. Speakers will get a yellow light two minutes before the end of
> your presentation and then a red light at the very end of your
> presentation.
>
> There will be some periods of time for discussion this morning. We are
> going to follow the same schedule as everyone has received and as is
> out there on the table. There have been no changes to this point in
> the schedule so we will start out with about a half hour or so to
> continue some discussion from yesterday, then we will have
> presentations from our sponsor at 8:45 and the schedule will continue
> like that.
>
> Today is nominally a day to discuss the Palladone risk management
> program, however, there are still general issues from yesterday that
> need to be discussed so I will try to be clear during the discussion
> period, and I think the questions are clear enough themselves, as to
> whether we are talking about general issues on risk management
> programs or the Palladone program in particular. I have no other
> general comments. Bob Rappaport or any of the folks from FDA, anything
> to add? If not, Johanna Clifford will read the conflict of interest
> statement.
>
> **Conflict of Interest Statement**
>
> MS. CLIFFORD: Thank you. The following announcement addresses conflict
> of interest issues with respect to this meeting and is made part of
> the record to preclude even the appearance of impropriety at this
> meeting.
>
> The conflict of interest statutes prohibit special government
> employees from participating in matters that could affect their own or
> their employers\' financial interests. All participants have been
> screened for conflict of interest in the product, competing products
> and firms that could be affected by today\'s discussions.
>
> In accordance with 18 U.S. 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 include Dr.
> Nathaniel Katz for consulting on an unrelated matter for the sponsor.
> He earns less than \$10,001 per year. Dr. Robert Dworkin for
> consulting on unrelated issues for three competitors. He earns less
> than \$10,001 a year from each firm. Dr. Steven Shafer for consulting
> for a competitor. He earns less than \$10,001 per year.
>
> 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 disclose 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 a shareholder.
>
> In the event the discussions involve any other products or firms not
> already on the agenda for which an FDA participants 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 other participants, we 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. Thank you.
>
> **Committee Discussion**
>
> DR. KATZ: Thank you. Now we have about 40 minutes of time to continue
> our discussion from yesterday. If everybody around the table could
> return to their list of questions, we will be continuing our
> discussion of question one which we were able to begin very briefly
> towards the end of the day yesterday.
>
> I will read the question. Please discuss the role of the potent
> modified-release opioids in the management of chronic pain. We can
> just begin a general discussion or continue a general discussion of
> that issue. Does anybody from the FDA side want to add any clarifying
> comments to that question, or are you satisfied with beginning a
> general discussion?
>
> DR. RAPPAPORT: Why don\'t we just begin with a general discussion and
> if we feel the need to jump in, we will?
>
> DR. KATZ: We are open for comments. Yes, please, Dr. Rose?
>
> DR. ROSE: Yesterday you had asked several questions about certain
> types of patients, certain patients at high risk for adverse events,
> etc. and I wanted to put my two cents in on that.
>
> I felt that when you talk about types of patients we should also talk
> about the physician doing the prescribing who needs to identify and
> document, if necessary of patients who in the past, when they have
> cared for them, have been unreliable and non-compliant. I think that
> is the issue. Cases that I have seen can kind of tell you in advance
> that these patients are going to have problems with the type of drug
> that we are talking about today. So, I think it is very important for
> the physician to actually evaluate the patient for their reliability.
> That was one issue that I wanted to make a comment on.
>
> Then the other, when you are going to say about the duration of
> treatment\--you are going to be getting to that, I know\--in the past
> there have been issues of putting a time limit on certain types of
> care that we give to patients who are considered to be terminally ill.
> There is, for example, the issue that hospice is only for patients who
> you expect not to live more than six months but, as was mentioned
> yesterday, many times if you appropriately treat a terminally ill
> patient you can actually extend their life and make their life more
> comfortable for whatever time they have left. So, I do think it might
> be inappropriate to put a time limit or to say if you don\'t expect
> the patient to live more than a certain period of time that this
> patient is a candidate for this drug and not otherwise. So, I don\'t
> think that we should put a time limit for terminally ill patients.
>
> DR. KATZ: Thank you. So, if I take your two points, you are suggesting
> that, number one, in assessing the appropriateness of long-term
> therapy one factor is assessing the likelihood of patient compliance
> with that therapy.
>
> DR. ROSE: Correct.
>
> DR. KATZ: One element in that assessment is history of compliance or
> non-compliance.
>
> DR. ROSE: Thank you.
>
> DR. KATZ: Then, the second point that you are suggesting is that in
> the course of appropriate medical practice artificial limitations on
> the duration of therapy are not part of normal medical practice with
> opioids.
>
> DR. ROSE: That is correct.
>
> DR. KATZ: Other comments? Yes, Dr. Baxter?
>
> DR. BAXTER: Thank you very much. I am glad to see that on my first
> attempt today I am in, not that I am still thinking about yesterday\--
>
> DR. KATZ: God forbid!
>
> \[Laughter\]
>
> DR. BAXTER: But I think that it is important from an addiction
> standpoint that part of the appropriateness that should be considered
> by physicians if in fact, number one, that there is a history of
> addiction or use disorder and, number two, what is the current status
> of that medical problem. It is my belief, and the belief of many
> addiction specialists, that people who have histories of addiction are
> not automatically excluded from use and benefit of opiate medication,
> but it is very important to be able to ascertain that person\'s
> recovery status.
>
> DR. KATZ: That is very helpful. So, again, you are suggesting that an
> addiction history should be a standard element and in good practice is
> a standard element of assessing a patient for the appropriateness of
> opioid therapy. I wonder if you could expand on that and maybe give us
> a little bit more information on what physicians do to get an
> addiction history and the accuracy of those office-based methods in
> obtaining an adequate addiction history.
>
> DR. BAXTER: The first thing is that the questions have to be asked.
> Unfortunately, I know that many times an addiction history is not
> taken. So, one would minimally need to ask if, in fact, a person has
> ever had any problems with drugs and/or alcohol. If the answer is yes,
> well, then further information needs to be gathered in terms of what
> substance was the drug of choice; what measures in terms of treatment
> were employed; and what the person\'s current recovery status is.
>
> DR. KATZ: What if the answer is no?
>
> DR. BAXTER: Well, then you have to figure out how far you really want
> to go with that line of questioning. As an addiction specialist, of
> course, you know that I would go much further but I think that in
> terms of primary care or general practitioners who, we all know,
> prescribe a lot of these medications we have to at least get them to
> start asking questions.
>
> DR. KATZ: Thank you. Dr. Dworkin?
>
> DR. DWORKIN: I have a question about the question. The question seems
> to emphasize the word \"potent\" and I don\'t think we have discussed
> that. Given a range of potency in the available modified-release
> opioids is the potency, meaning the milligrams needed for an
> equianalgesic dose, relevant in any way at all or not to clinical
> practice of these modified-release opioids. So, I guess my question is
> about have we really discussed potency variability among these drugs?
> And, I don\'t think we have, and should.
>
> DR. KATZ: So, are you asking the question about whether the word
> \"potent\" changes the answer here?
>
> DR. DWORKIN: Yes, whether the potency of the drug change has any
> impact on the answer.
>
> DR. KATZ: Or, are we just really discussing about opioid therapy in
> general? Well, that is a question and that is open for commentary. Is
> the standard of practice different for opioids depending on their
> potency? Dr. Saini and then Dr. Shafer?
>
> DR. SAINI: I think the WHO letter was made on an arbitrary basis.
> There is really no difference between a weak opiate and a strong
> opiate. You can give enough of a weak opiate and get the same effect
> as compared to giving a smaller amount of a stronger opiate. So, the
> main question is should the opiates be used in pain. And, the answer
> is, yes, if appropriately used they are the gold standard for moderate
> to severe pain while NSAIDs should be used to control mild to moderate
> pain.
>
> Having said that, the risk of addiction should be assessed and at the
> same time the adverse effects of narcotics should be assessed also as
> the therapy is going on. While you are assessing these risks, when you
> see these drug addicts nobody will divulge a history that they have
> been in a drug rehab program. It is usually later on that you find
> that these people have been in a drug rehab program and you have
> problems. So, assessing the history and if they are prone to becoming
> an addict is important. Family history of drug dependency, history of
> anxiety, depression, psychiatric disorder and previous history of drug
> abuse makes them more prone to become a drug addict.
>
> DR. KATZ: Thank you. Dr. Saini, your answer to Dr. Dworkin is no. You
> are saying that the word \"potent\" could just as easily be taken out
> of this question and that the standards of care and medical practice
> are the same for all opiates, regardless of their potency or their
> release. Am I understanding you correctly?
>
> DR. SAINI: That is correct.
>
> DR. KATZ: Dr. Shafer?
>
> DR. SHAFER: Dr. Dworkin\'s question is a good one. I think it relates
> to the fact that there are two definitions of potency that are used.
> To the lay public potent just means strong and the strength has two
> components. One, from a pharmacological perspective, is the
> concentration associated with 30 percent maximum drug effect, which is
> the definition you are thinking of, and that is absolutely irrelevant
> to the utility of the drug provided you don\'t have to eat, you know,
> bricks of the stuff to get a drug effect. The other is the intrinsic
> efficacy, the maximum effect the drug can produce, and all of the full
> mu agonists are thought to pretty much go to the same maximum drug
> effect.
>
> From a pharmacologic perspective, I think what we are talking about is
> the full mu agonists. If we want to be true to what we are talking
> about here pharmacologically, we should perhaps talk about full mu
> agonists and leave potency out of it. I think potency is being used in
> a colloquial sense.
>
> DR. KATZ: So, your answer is also no to Dr. Dworkin?
>
> DR. SHAFER: Yes.
>
> DR. DWORKIN: Can we ask the Division whether potency is being used in
> a colloquial sense or in a pharmacologic sense in this question?
>
> DR. KATZ: Yes, you can.
>
> DR. DWORKIN: Thank you.
>
> DR. RAPPAPORT: Thank you. This question refers to the use of the high
> dosage, extended-release opiate products that are under discussion as
> a general topic of the meeting.
>
> DR. KATZ: Maybe I can clarify that. Correct me if I am wrong, I think
> the question was worded this way because that is what we are here to
> meet about and it doesn\'t in any way mean to exclude other forms of
> opioids or get into the issue of whether the practice standards might
> be different. Is that fair enough?
>
> DR. RAPPAPORT: Yes, although we would like to have some focus on that
> particular group of drugs as it applies to this meeting and also as it
> applies today to the ensuing discussion of Palladone.
>
> DR. KATZ: Yes, I think what we are hearing, so far anyway, from the
> group is that the practicing patterns and standards are the same
> regardless whether the opioid is more or less potent or modified
> release or not modified release, if I am hearing the committee
> correctly. Does anybody think I am hearing wrong? Dr. Bril?
>
> DR. BRIL: My comment was more in the form of a question to individuals
> running pain clinics; as I say, I run a more general clinic. This
> applies to opiate therapy and disclosure with the patient and exactly
> how the therapy is phrased to the patient. I think it is important, in
> chronic pain particularly, that the patient really be aware of the
> class of drug they are taking. I mean, opiate may mean a lot to us and
> so may pain killer but to the patient I think even being very blunt
> and telling them they are taking a narcotic, with all the implications
> that has, is something that may be considered because a lot of
> patients won\'t really know what you mean if you just say opiate and
> if you say pain killer, there are so many it is a non-specific term.
>
> So, for me, when I start a patient on this, because there is no
> definitive way that I have of knowing who would be addicted, if I
> select the patient and think that they are safe candidates for this
> kind of therapy I do warn them about the class of drug I am using with
> them. I just think that caution and full disclosure in a way that
> patients will truly understand are necessary.
>
> DR. KATZ: So, you are suggesting that in prescribing these medications
> to patients, just calling them pain killers without being more
> specific about their class and their potential risk is not sufficient.
>
> DR. BRIL: True. I mean, a nonsteroidal is a pain killer, or aspirin is
> a pain killer if we use it in certain ways, which are quite different
> from opiates. And, using the word opiate isn\'t necessarily enough
> either, although you might think it is.
>
> DR. LEIDERMAN: First a comment and then a question. I think that it is
> important when we talk about pharmacologic potency to think about the
> multitude of effects that drugs have, and equianalgesia does not
> necessarily equate to equal effects in terms of psychic effect,
> euphorigenesis, reinforcing effects. We will come back to that with
> some data to be presented later this morning, but that is a part of
> the very complex concept of potency and I think that that is part of
> what we mean.
>
> The question part, I would ask the pain doctors here, I mean, do you
> prescribe Dilaudid in the same way that you prescribe a codeine 30 mg?
> I would suggest not and it doesn\'t have to do just with the different
> dosage strengths available. So, that is sort of my comment.
>
> My question is about something touched upon yesterday that I would
> like to have a little bit more input on. What does the committee think
> is the role of physician-patient care contracts in the context of
> chronic, non-malignant pain treatment with high dose opiates?
>
> DR. KATZ: Let\'s leave that question in the air. I want to make sure
> that I am not missing people who are on line for comments. Dr.
> Gillett, you are next.
>
> DR. GILLETT: When you are a layman this whole business of indication
> is a very difficult proposition. After you have questioned your
> patient and discussed their addiction, what choices do you have? Do
> you withhold from a patient who has gotten squamous cell carcinoma as
> a consequence of alcoholism? You are going to withhold a pain killer
> like one of these medications during radiation therapy when they elect
> not to have surgery because their physician had a TV show and
> testified in court about drug addiction and alcohol and drug-driving
> cases? In other words, a friend of ours down in Greenville, South
> Carolina is faced with this and he receives OxyContin.
>
> DR. KATZ: It sounds like you are agreeing with Dr. Baxter that one
> needs to do a risk assessment and that some patients may be at higher
> risk for complications, but that doesn\'t necessarily equate with
> withholding therapy. Maybe what we will get to in some point of our
> discussion is, well, what does that equate to? What does one do in
> that situation? Let\'s see, Dr. Skipper, you were next.
>
> DR. SKIPPER: Because we are here primarily, in my view, to talk about
> the risk of these drugs and the primary risk that we are concerned
> about is the spiking epidemic abuse and the recruitment of new addicts
> who take these drugs, some of whom die from overdose, going back to
> the end of the day yesterday when you asked about mild, moderate or
> severe and I was looking toward possibly encouraging a change in that
> terminology, which I have now decided maybe to give up on, I would
> subsequently like to see more of a move toward restricting the use for
> severe pain, if we define severe pain as significant impairment of
> function, because I think we need to decrease the amount of these
> drugs on the market because that will decrease the epidemic of abuse.
>
> DR. KATZ: Won\'t you expand then on how you would propose implementing
> that sort of an approach?
>
> DR. SKIPPER: Well, I would suggest that the package insert say that
> these drugs, these potent extended- release opioids be used for severe
> pain, and then define severe pain as significant decrease in function
> associated with pain.
>
> DR. KATZ: Of course, we have an ambiguity because most
> practitioners/researchers use the term mild, moderate and severe as a
> measure of pain intensity on some sort of scale, so you would
> introduce the term but then redefine it in a way different from its
> customary use, focusing more on impact. But I still would, you know,
> be interested in hearing you expand more on this notion of impact on
> function as being a marker of the importance of the disease to the
> patient and the importance of treating it aggressively.
>
> DR. SKIPPER: Well, as I said yesterday, I think the way we monitor
> whether these drugs are effective is by looking to see if function
> improves. If function is not impaired, then I am not sure they should
> be used. So, I would like to see movement towards some kind of policy
> that function be assessed. Because that was not received well, then I
> am thinking that to redefine mild, moderate and severe so that that it
> be associated with significant decrease in function may restrict to
> some degree the use of these, which would decrease the problem of
> substance abuse.
>
> DR. KATZ: So, just to clarify what you are saying, it sounds
> like\--correct me if I am wrong\--is that even somebody whose pain
> intensity level was rated using the word moderate but, yet, that pain
> still had an impact on that patient\'s ability to function they would
> be a candidate for opiate therapy in your mind because they would be
> reclassified as severe based on your impact definition.
>
> DR. SKIPPER: I guess that is correct.
>
> DR. KATZ: Thank you. Dr. Ciraulo, you were next.
>
> DR. CIRAULO: Yes, Dr. Leiderman had addressed some of the issues that
> I wanted to raise but I wanted to go back to the issue of potency. I
> think that what we are really talking about is abuse, liability and
> concerns about that and I think that, yes, it is correct that most of
> the drugs we are talking about are full mu agonists. We also have to
> think about the pharmacokinetics of these drugs. If you look at abuse
> liability across substances of abuse, you know the drugs that are more
> rapidly absorbed and reach higher peaks are subject to greater abuse
> liability.
>
> I think there are differences among the opioids. Certainly, in the
> days when I did physician management of addicted physicians there were
> patterns. There were certain drugs that were preferred, and I think
> they correspond with a lot of the PK of the full mu agonists and I
> think we have to keep that in mind as we look at the data.
>
> I just wanted to add that I certainly support the use of these drugs
> in recovered substance abusers. I think you should do an assessment.
> You will make mistakes. I want to emphasize that when mistakes are
> made people should not be prosecuted for these mistakes; this is going
> to be part of the practice, but denying substance abusers who are in
> stable recovery adequate pain management is inappropriate.
>
> DR. KATZ: So, you are then joining those who have said that while risk
> assessment, including a substance abuse history, is important. That
> doesn\'t mean that the patient should necessarily be excluded from
> opioid therapy as a result of that assessment. So, what are the
> implications then for the use of opioids in such patients? If we are
> taking their history and identifying their risk level are there any
> implications for management?
>
> DR. CIRAULO: Yes, definitely. I think you have to step up
> surveillance. I realize that this would be a problem in some rural
> areas, and I don\'t work in a rural area so I don\'t have specific
> suggestions for that, but in areas where there are specialists I think
> with more frequent visits, good contact with pharmacy, single-source
> prescribing, and a lot of the things that we can do to monitor we can
> build in good surveillance programs so that even if a substance abuser
> does end up having any problems initially, I think it is inappropriate
> to say, \"okay, you\'re out.\" I think there should be an algorithm to
> step up the surveillance.
>
> DR. KATZ: So, you are saying that patients who are identified as being
> at higher risk, even if they are prescribed opioid therapy, need to be
> prescribed it in a different sort of program than somebody without
> those red flags for risk.
>
> DR. CIRAULO: Exactly. What we have done in the past\--and I am not
> saying we want to do this in the future but in the past we have put
> such patients in methadone clinics. I am not sure I would do that now;
> I think there are better ways to do it.
>
> DR. KATZ: Thank you. Next was Dr. Strom.
>
> DR. STROM: A couple of related comments. I am a general internist; I
> am not a pain expert and I certainly have no problem with the clinical
> recommendations I am hearing and referring my pain patients to
> colleagues. But as an epidemiologist, my role is to be a curmudgeon,
> and part of my concern about what I am hearing is that I would ask my
> fellow committee members to differentiate when what you are saying is
> based on data versus when it is based on opinion. It is not clear to
> me virtually any of this is based on data and I think it is important
> we make that clear when we give this advice to FDA because FDA is a
> science-based agency and needs to make its decisions according to
> that, and that ranges from clinical recommendations to recommendations
> about risk assessment to try to predict addiction and thinking we
> really have the ability to do that to recommendations about even
> restricting use and that that would in any way affect the amount of
> addiction in society. I am not sure we have heard the data to underlie
> any of that.
>
> DR. KATZ: Thank you. I think that is a very important point and I want
> to get back to it but first Dr. Jenkins.
>
> DR. JENKINS: I would like to offer the committee some clarification on
> what the intent was of this question because I think you are verging
> into a much more general discussion about the role of opioids in
> treatment of pain. We were really focused on what is the role of
> sustained- release or modified-release opioids in the treatment of
> chronic pain. There have been some, for example, who have argued that
> these products are simply convenient dosage forms and, therefore, the
> abuse liability and the abuse potential and the actual abuse we have
> seen negates the value of these products to the patients. So, our
> focus of this question was not to get into a general discussion of
> when should you use opioids in the treatment of chronic pain. It was
> more to ask you to talk to us about the role of sustained- or
> modified-release opioids in the treatment of chronic pain. So,
> hopefully, that can help you focus your discussion so that we can get
> back from you all that we are looking for.
>
> DR. KATZ: Thank you for that clarification. Let\'s then look at the
> discussion in a different way and open up the floor for comments on
> the particular role of modified-release opioids in the opioid
> management of patients with chronic pain.
>
> Actually, as long as we are pausing for a moment, Dr. Leiderman did
> put this question in the air about the use of patient care agreements.
> So, in light of this refocused discussion, does anybody have any
> comments on patient care agreements? Go ahead, Dr. Rose.
>
> DR. ROSE: I get to look at liability insurance claims and sometimes I
> see anesthesiologists or other physicians who have had problems where
> there are not contracts. I can see situations where had this physician
> used a contract and insisted that the patient comply we wouldn\'t have
> the problems. I am very much in favor of physician and patient
> contracts.
>
> DR. KATZ: For medical-legal reasons, it sounds like you are saying.
>
> DR. ROSE: Yes, for medical-legal reasons and also I think it helps the
> physician to help the patient. I think that contracts are very, very
> important.
>
> I would like to make a comment about this issue of the concept of
> sustained release. The concept of sustained release I think is great.
> If we were talking about a drug for sustained-release management of
> hypertension I think all of us around the table would think that is
> great because if you want someone to take a pill four times a day to
> manage their hypertension, that is a problem because it is just hard
> to do. The issue here is sustained release for opioids, and then the
> reason why we are looking at that in a more focused way is because of
> the problem of abuse and inappropriate use of the drugs. So, I think
> that really our focus needs to be on how can we handle that abuse
> because underlying it all I think most of us would agree that
> sustained release anything is a good idea because it helps in better
> patient care.
>
> DR. KATZ: Dr. Kahana?
>
> DR. KAHANA: I would like to reiterate from a non-epidemiologist what
> Dr. Strom had said because I feel like I am in a very awkward position
> of trying to come up with recommendations with remarkably little real
> data. I guess the question I would have is would we be better off
> trying to define the patients who are not good candidates for these
> drugs rather than the ones who are, and to define a subset of patients
> who might be better off referred to people who are specialists, either
> by direct referral or by telecommunication. We certainly have the
> ability to encompass an enormous geographic area with expertise, if
> not by direct patient contact at least by telecommunication with
> someone who is an expert. Could we not provide a mapping system for
> people who would have the ability to access the experts in this kind
> of drug dispensing? Because the restriction of this class of drugs to
> those who really have chronic and sustained pain, malignant or
> non-malignant in its origin, I think would be a real serious error
> based on at least the data we have seen, which would lead me to
> believe that 50 percent of perioperative patients are getting the
> sustained-release preparations which, I must say, I am a little
> skeptical to believe. So, even the data I think we have seen is
> questionable at best.
>
> DR. KATZ: Yes, Dr. Ciraulo?
>
> DR. CIRAULO: Since you have redirected that, I would like to
> re-approach the issue of the addicted patient. I have two comments and
> questions. One is if we believe\--and this is a question\--if we
> believe that these drugs, these long-term and immediate-release drugs
> are different in their abuse liability, if we say the drugs we are
> evaluating have higher abuse liability, would the pain people feel
> comfortable saying that this would not be a first-line drug for pain
> management in someone with a history of substance abuse? That is part
> one.
>
> The second part is if you use these drugs, do the pain experts have an
> idea of what the risk is of creating a new addict in the patients they
> treat?
>
> DR. KATZ: That was a complicated question and comment but it sounded
> like the first part of it was sort of a question about whether the
> modified strong-release opioids have a higher abuse liability than the
> immediate-release opioids. Was that the first part?
>
> DR. CIRAULO: Yes, the extended release, for example, can be chewed and
> has a very high abuse liability. It wouldn\'t be a drug that I would
> be inclined to prescribe for someone with an addiction history.
>
> DR. KATZ: So, maybe the first part of your question or statement is
> worth discussing, which is whether the modified-release opioids have a
> higher abuse liability or risk of harm should they be abused, or
> something like that. If so, does that imply some differentiation in
> how they should be used? You are suggesting perhaps in high risk
> patients that is one area of differentiation and maybe there are other
> areas of differentiation as well, but it seems like in either case it
> hinges on the notion of whether these medications do have a higher
> abuse risk than the immediate-release dosage forms.
>
> DR. CIRAULO: Yes.
>
> DR. KATZ: Maybe we should discuss that. That seems to be a relevant
> issue to the current question. Do people have comments on whether
> these modified-release dosage forms have a higher abuse risk than the
> immediate- release forms? Dr. Maxwell?
>
> DR. MAXWELL: Well, yesterday we had a significant amount of data
> presented showing increases in the emergency room episodes and
> treatment admissions with the introduction now at least of OxyContin.
> I think some of these increases are due to that.
>
> What we haven\'t talked about, which concerns me, is not the pain
> patient who, I agree, needs the medication but the unintended
> consequence of creating another pool of patients who are addicted drug
> users who previously were not addicted until they used OxyContin. So,
> I think we need to look at what are the unintended consequences. It is
> not just a new and better medication for patients who need it, but we
> have created a whole new population of users and we are paying the
> cost because we are now having to provide drug treatment to this
> group. So, there is another aspect to this.
>
> DR. KATZ: So, there is one question in the air, which is are these
> modified-release forms a higher abuse risk than the other forms? You
> have also echoed another of Dr. Ciraulo\'s questions, which is what is
> the incidence of creating new patients with the disease of addiction
> based on therapeutic exposure to these drugs? I think both of you were
> asking that question and implying that these are important things we
> need to know in order to create appropriate standards of practice. Dr.
> Strom?
>
> DR. STROM: I think it is important, looking at the data that we saw
> yesterday, that we realize that almost all of it was numerator data.
> We saw a lot of increased abuse, illness, admissions and so on, but
> the denominator data were increasing equally dramatically. There was
> also a lot of increased use of these sustained-release drugs and it is
> not at all clear to me from the data that we saw that that indicates a
> higher abuse potential. In fact, OxyContin represents a very small
> proportion of all of the abuse that is out there. So, it is important
> to look not just at the numerator data but also denominator data
> before drawing any conclusions.
>
> DR. KATZ: Dr. Dworkin?
>
> DR. DWORKIN: It seems to me there is another way of addressing Dr.
> Jenkins\' question in relation to whether the modified-release opioids
> are associated with greater abuse liability, and that is whether there
> are any data in head-to-head comparisons of modified release with
> immediate release to suggest a benefit on any endpoint of the modified
> release.
>
> I have been perseverating on that issue because I don\'t know, other
> than a kind of broad overview of the data, the real results. It seems
> to me those must be incredibly difficult studies to do because if you
> do it in a double-dummy way you lose the convenience of the modified
> release because every patient is taking both drugs p.r.n. or q.i.d.,
> and if you don\'t do it in a double-dummy way and patients and
> investigators know whether they are doing b.i.d. dosing or q4 or q6
> dosing, it is not a double-blind trial. But it seems to me that that
> would be a very important set of data to know about, if it exists, and
> if we could get over these methodological issues because I hear your
> question as asking are there any benefits in the literature of
> modified release versus what we had before in 1995. And, I just don\'t
> know the answer to this question but I despair that the studies can be
> designed in a way to really answer it.
>
> DR. KATZ: So, you are asking yet a third question which we are getting
> on the table. We are getting all these questions and no answers from
> this committee. But your third question is what is the evidence base
> for the benefit of the modified-release opiates over immediate-release
> opiates. Dr. Shafer?
>
> DR. SHAFER: Thank you. Let me just read here from Jim Zackney, \"Drug
> and Alcohol Dependence,\" 2003, this is a consensus statement from the
> College on Problems of Drug Dependence: At present, it is almost
> impossible to separate the risk of abuse from the therapeutic action
> of opioids. So, hopefully, there is one answer.
>
> By the way, I put the same question to Art Lipman yesterday, is there
> any difference between the therapeutic action in terms of potency and
> abuse potential, and he also said absolutely not. So, the answer to
> that question by two people who are quite expert and publish here is,
> no, there is no difference in abuse potential related to the molecule
> per se. Now, there may be differences in prescribing patterns,
> variability and things like this and, you know, street fads but the
> pharmacologic answer appears to be no.
>
> DR. KATZ: As you said though, that doesn\'t really get to the question
> of if there are any differences in the abuse liability of the
> modified, high potency formulations we are talking about. It is the
> molecule part of the question that that seems to be addressing.
>
> DR. SHAFER: Interestingly, as you pointed out, people have associated
> rapid blood-brain equilibration with abuse potential. People like the
> sense of giving a drug and, whoosh\--you know, you are high
> immediately. I infer from what I have read about these drugs that they
> are intended to get around that, to not have this rapid onset.
> Actually, they have lower abuse potential. The fact that these drugs
> appear to have been abused more is in line with their overall
> properties rather than their pharmacokinetic profile suggests, that
> there is no difference one way or the other. Certainly, the benefit
> that was envisioned for slow onset was not appreciated.
>
> DR. KATZ: It is time for our sponsor presentation but just for me to
> wrap up our collective wisdom for the moment, it seems that in
> attempting to discuss the role of modified-release opioids as distinct
> from other opioids at the moment we have basically three questions on
> the table and we have constant pressure, as we should, to make sure
> that our answers are evidence based or at least that we should
> understand the difference.
>
> One question is whether the modified-release opioids have higher abuse
> risk, abuse liability, and I am deliberately being vague about what
> term I use, than the other opioids and that seems to be still a
> question on the table which, hopefully, we can get back to later.
>
> The second question is what is the incidence of new addictions based
> on medical exposure to these medications, and that remains a question.
>
> The third is an even larger question perhaps, which is what is the
> benefit of these medications over previous forms and what is the
> evidence base underlying the notion that there is a benefit?
>
> Those are questions that the committee has not gotten to trying to
> answer yet. Any FDA comments prior to moving on to the sponsor
> presentation?
>
> \[No response\]
>
> Well, our first presentation then, if everybody is ready, will be from
> Dr. David Haddox who will be speaking with us on Palladone capsules
> for the management of persistent moderate to severe pain in
> opioid-tolerant patients. Dr. Haddox is a long-standing contributor to
> this field and is currently vice president of health policy at Purdue
> Pharma L.P.
>
> **Sponsor Presentation**
>
> **Palladone Capsules for the Management of Persistent**
>
> **Moderate to Severe Pain in Opioid-Tolerant Patients**
>
> DR. HADDOX: Thank you very much, Mr. Chairman. Members of the
> committee, the members of the agency who are here, thank you for the
> opportunity to address you this morning.
>
> \[Slide\]
>
> I want to go over some of the highlights of our risk management
> program for Palladone capsules and sort of bring to focus some of the
> issues that are in your briefing document. It will come as no
> surprise, given the discussion yesterday, that we, at Purdue, believe
> that we have some considerable experience in risk management with
> modified- release opioids and I would like to share how our thinking
> is evolving there.
>
> \[Slide\]
>
> The speakers in this one-hour session will be myself, Dr. Sidney
> Schnoll, who is a noted addiction expert and researcher, and Dr.
> Herbert Kleber, who is also a noted expert in substance abuse
> treatment and research and is also the former deputy director for
> Demand Reduction in the White House Office of National Drug Control
> Policy.
>
> For those of you who don\'t know me, just a moment about myself. As
> you can see, I started out my professional life as a dentist. I then
> went to medical school. I have done combined residency in
> anesthesiology and psychiatry with the idea of becoming a pain
> physician. I have also received certification in addiction medicine
> along the way.
>
> \[Slide\]
>
> In addition to the three speakers, we have three of our consultants
> with us, Dr. Theodore Cicero, who is vice-chancellor for research at
> Washington University and one of the principal investigators in our
> signal detection component; Dr. James Inciardi, from the University of
> Delaware, also a principal investigator on another component study;
> and Dr. Richard Dart, from the University of Colorado and the Rocky
> Mountain Poison Control and Drug Center, who was another principal
> investigator.
>
> \[Slide\]
>
> You have been exposed to a lot of material. I heard some comments
> during the discussion yesterday that it seems to be somewhat
> overwhelming; I hope you have had your coffee this morning. I will try
> to pace you through this and, hopefully, keep things on track.
>
> I am going to make a few introductory comments and then I am going to
> briefly review Palladone capsules as a specific drug product for you,
> then go through the risk management program, highlighting our goals
> and objectives, some of the elements, and giving you some examples of
> some of the tools that we are using. Then Dr. Schnoll will talk to you
> in some detail about the surveillance component, the RADARS system
> and, finally, Dr. Kleber will end with his observations from his
> 35-plus years of drug abuse treatment and drug control policy, and
> make some observations for you.
>
> \[Slide\]
>
> Our position on risk management programs for opioid analgesics is
> that, first and foremost, they must protect patients. We must try to
> mitigate the risk of using these medications in the specified
> population for the specified indication. We must always balance the
> legitimate needs of patients against the risks posed to abusers.
>
> We believe that risk management programs are needed for all opioid
> analgesics. We believe that they must be consistent within a schedule
> of the controlled Substances Act. That is, Schedule II risk management
> programs should have certain common elements and Schedule III programs
> should have certain common elements.
>
> It is extremely important in contemplating this, given the environment
> into which new opioid analgesics will be introduced, that we think
> about three distinct populations, patients who have a need for and
> deserve good pain care; abusers who need to be prevented, if at all
> possible, before they become abusers and certainly need treatment once
> they become abusers; and criminals who prey on the abusers who need to
> be stopped.
>
> \[Slide\]
>
> We further believe that no single group can implement an effective
> risk management program for opioid analgesics that addresses all three
> populations. This is a shared responsibility that requires a
> multifaceted effort of coordination, cooperation and consistency from
> industry, from regulators at the federal level and also at the state
> level as in licensing boards, and all the other stakeholders here.
> Part of what I would like to do in the presentation is show you how we
> have worked thus far with our ongoing risk management program with
> some of these various stakeholders.
>
> \[Slide\]
>
> Now let me briefly review for you Palladone capsules.
>
> \[Slide\]
>
> You have heard the discussion today and yesterday that oral opioid
> analgesics are an effective therapy for appropriately selected
> patients; that modified-release opioids have been proven safe and
> effective in those patients. However, due to variability of response
> to opioids and the need for individualized treatment strategies,
> healthcare professionals need a variety of opioid formulations.
>
> \[Slide\]
>
> Palladone capsules, in our approvable letter of September, 2002, were
> deemed to be safe and effective by the agency. They contain lots of
> little hard pellets, each of which has hydromorphone hydrochloride
> embedded in an extended release matrix. That is, if you pull a capsule
> apart and these little pellets fall out, each of those is its own
> extended release delivery system, in contradistinction to OxyContin
> for instance.
>
> Hydromorphone is a full mu agonist with reported equianalgesic potency
> compared to morphine, ranging from 1:3 to 1:10 by the oral route.
> There is a great deal of variability. It is formulated for once-a-day
> administration and it is going to be launched in a variety of
> strengths to allow easy titration for the physicians.
>
> \[Slide\]
>
> The benefits of Palladone capsules provide the healthcare
> professionals with an important therapeutic option. It will be the
> only extended-release hydromorphone in this country. The once-a-day
> administration is for the convenience and compliance, for instance,
> the elderly patient who might have difficulty remembering when to take
> medications and needs, like my mother, to have my sister call her and
> say, \"hey, mom, did you take your medicines this morning?\" For
> analgesia she just needs that one phone call.
>
> It provides a choice among extended-release opioids. You have heard
> some comments today and pain clinicians on the committee know that
> when we are treating patients, as I did for much of my professional
> life, not everyone responds to everything the same way. We need to
> have a large pallet at our disposal to make sure that we can optimize
> care for a given individual.
>
> The contents\--as I mentioned before, the capsules can be pulled apart
> and the contents, little pellets, can be sprinkled on soft food. Think
> of the advantage in the case of a person with swallowing difficulty, a
> person with scleroderma for instance, or a person with esophageal
> stricture or radiation results from head and neck surgery, this is
> going to be a real advantage for these people.
>
> And, it may just simply be the best choice for some patients, as was
> validated in our clinical trials where we had a number of reports from
> the investigators saying that this was really the right drug for that
> patient.
>
> There is less fluctuation in blood levels compared to
> immediate-release hydromorphone and I will show you a PK slide.
>
> There is no food of pH effect, which is a distinct benefit. We have
> studied this in cancer and non-cancer pain in doses ranging from 12 to
> 500 mg/day.
>
> \[Slide\]
>
> At steady state Palladone, which is in the yellow here, compared to
> the equivalent daily dose of immediate- release hydromorphone given,
> of course, several times a day, you see lower peak-to-trough
> variability, essentially a smoother curve as one would expect from a
> modified-release formulation.
>
> \[Slide\]
>
> I now want to talk about the risk management program itself. It is
> important again to remember the thesis, that we want to have the
> benefits for the intended patient population for the intended
> indication balanced against the risks not only for the intended
> population but also for these unintended populations.
>
> You will also notice as I go through this, keeping in mind those three
> groups, patients, abusers and criminals, that there are
> Palladone-specific elements to this risk management program even
> though there are also common elements with our OxyContin risk
> management program because the common elements are to address the
> abusers and the criminals because these are system-wide problems; they
> are not limited to a single drug or formulation. The
> Palladone-specific elements are to address the intended population for
> this particular formulation.
>
> \[Slide\]
>
> As was mentioned yesterday, Research!America has come up with a pool
> very recently showing that despite the fact that we are in the
> congressionally determined decade of pain control and research, if you
> look systematically at the surveys of pain prevalence, particularly
> under-treatment of pain in this country, not much has changed in the
> last 15 years. Yet, while Palladone will be one of the tools to help
> meet this need in appropriately selected patients, it will be entering
> into an environment that we have already heard a lot about yesterday.
>
> \[Slide\]
>
> These are the number of new or first time non-medical users of pain
> medicines. You can see here that from 1980, just in five-year
> increments, there was a significant problem in the \'80s, that the
> problem doubled between \'90 and \'95 and doubled again between \'95
> and 2000.
>
> \[Slide\]
>
> It is also known from these data that, if you look, there is not one
> single opioid that seems to be the problem, or even one single
> formulation of the branded hydrocodones compared to other
> hydrocodones.
>
> \[Slide\]
>
> It is also critical, when you are looking at these data in your
> briefing document, to make sure that you follow the somewhat peculiar
> or at least particular way that these data are presented and that
> lifetime prevalence is in response to the question \"have you ever,
> even once in your lifetime used a drug that was not indicated for you
> or wasn\'t prescribed for you or for the feeling it caused?\" \"Past
> year\" gives you an example of sort of point prevalence over a year
> and \"past month\" is defined or is thought to be the proxy for
> current use. So, these are very different figures and I just want to
> call that to your attention because it is easy to get lost in these
> data.
>
> \[Slide\]
>
> As part of our risk management program, in addition to reviewing these
> various surveys, we have also done some analysis where we asked for
> specific data runs. I just want to share with you this analysis
> looking at the people who admitted to any lifetime non-medical use of
> hydromorphone compared to those who said, \"no, I\'ve never
> non-medically used hydromorphone.\"
>
> What you see here on three parameters over three years, \'99 to 2001,
> is the percent using multiple prescription analgesics
> non-medically\--and multiple means two or more\--is about twice that
> in the group who admit to non-medical use of hydromorphone than those
> who do not admit to that use. Likewise, the percent using cocaine or
> heroin is about twice as many. If you look at the percent using
> needles, it is about 12 times as many people who say that they have
> any lifetime use of hydromorphone admit to needle use as opposed to
> those who do not have any lifetime use of hydromorphone.
>
> I believe that this is describing a distinct population that is very
> different from the patients that most of us are treating in a pain
> setting. These are people that are hard core drug abusers.
>
> \[Slide\]
>
> Let\'s talk about the pharmacological considerations for abuse
> liability of hydromorphone. When you look at the pharmacological
> profile, the propensity to induce tolerance, the propensity to develop
> physical dependence, it looks like morphine. When you look at the
> human and animal abuse liability studies, hydromorphone looks like
> morphine. There is no evidence in the scientific literature of
> differential abuse liability among full mu agonists and potency. As
> has been discussed this morning and a little bit yesterday, it is
> really irrelevant to abuse liability because the abuser will take the
> dose that they want, whether they take a little or whether they take a
> lot.
>
> \[Slide\]
>
> Specifically hydromorphone abuse liability, if you look in patients
> there is really no evidence in the literature of differential abuse
> liability compared to other full mu agonists. If you look in the
> abusing population there is no evidence of greater abuse liability
> compared with morphine. In fact, Preston and Jasinski, in a 1991
> review article of this literature, stated \"in all of the studies the
> profile of subjective effects of hydromorphone were similar to those
> previously reported for morphine.\" Of course, hydromorphone is a full
> mu agonist and in the abuse setting has all the risks of abusing any
> other full mu agonist, especially the risk of overdose and
> particularly when the abuse involved multiple drugs.
>
> When studying drug abuse deaths it is imperative to remember the
> caveat in the DAWN medical examiner\'s report that states \"when
> multiple drugs are involved in a single case, the cause of death
> cannot be attributed to any particular substance.\"
>
> As our recent study in the [Journal of Analytic
> Toxicology]{.underline} earlier this year showed, in 919 drug abuse
> deaths where oxycodone was detected, 96.7 of them involved multiple
> drugs, with a mean of 4.5 drugs of use per decedent and a range of
> 1-14 drugs.
>
> \[Slide\]
>
> These data are combined from two separate studies that we have done.
> One was an intravenous study and one was oral immediate-release
> hydromorphone single dose versus Palladone single dose. For the
> immediate release study, I want to call your attention to this, this
> part of the curve is missing. That is because in this particular study
> design, because of what we were looking for, the data point was at 30
> minutes so, obviously, this peak was much higher in the first few
> minutes but that is why the data point starts right there. This is the
> immediate-release and this is the extended-release hydromorphone.
>
> \[Slide\]
>
> In the risk management program our goals are basically three: to
> ensure proper use, that is the patient population; to reduce abuse in
> the abusers and potential abusers; and to minimize diversion and the
> attendant criminal activities that go along with that.
>
> \[Slide\]
>
> I would like to review for you the objectives of each of those goals.
> To ensure proper use, proper patient selection is one of the key
> objectives. We want to make sure that physicians know who is right for
> this drug and who is not. Once they have made the selection, we also
> want to know that they actually know how to use the drug, and we want
> to make sure that they know how to prevent unintentional exposure.
>
> \[Slide\]
>
> As far as reducing abuse, we are involved in a number of
> community-based interventions, which I will share with you, and
> healthcare professional education. We need to make sure that our
> healthcare colleagues understand the signs, symptoms and indicators of
> abuse and how to assess for abuse before putting a person on this
> medication.
>
> \[Slide\]
>
> To minimize diversion we are supporting law enforcement in some ways
> that I will give you some examples of. We have a very active supply
> chain integrity program to ensure that the program integrity is what
> is supposed to be as it leaves us and goes to the distributor. Again,
> healthcare education to help the healthcare individuals who are
> prescribing and dispensing these medicines understand what the
> criminal element is up to so that they can, hopefully, not fall victim
> to the scams.
>
> \[Slide\]
>
> These are some of the key elements of the risk management program. You
> have heard about Schedule II restrictions. I have mentioned briefly
> the supply chain integrity. Because this is a public hearing I don\'t
> want to talk in any more detail about that because I really don\'t
> want to tell people how to try and compromise our supply chain
> integrity.
>
> \[Slide\]
>
> So, let\'s focus on communication of key safety messages. There are a
> number of things that I want to highlight for you in this regard\--
>
> \[Slide\]
>
> \--the package insert for the prescriber or dispenser, the patient
> package insert for the patient or caregiver, medical communications
> that are outside the package insert and our promotional activities.
>
> \[Slide\]
>
> Let\'s focus on the proposed package insert. These are some of the key
> elements in it. Again, in the interest of time I am just going to
> highlight three. You heard about the CII designation yesterday; you
> know what that involves. I want to walk you through the boxed warning
> that we have proposed to the agency because I think this is the first
> thing the practitioner is going to see; this will be in the ads, etc.
>
> \[Slide\]
>
> Palladone, or hydromorphone hydrochloride extended-release, capsules
> are indicated for the management of persistent moderate to severe pain
> in patients requiring continuous around-the-clock opioid analgesia for
> an extended period of time. Palladone capsules should only be used in
> patients who are already receiving opioid therapy and who require and
> can tolerate a minimum total daily dose equivalent to 12 mg of oral
> hydromorphone.
>
> Thus, the practitioner has to meet a four-tailed test for the
> appropriate indication for Palladone. The pain must be moderate to
> severe. It must require continuous around-the-clock opioid analgesia
> because there are moderate pains that may not require that. And, it
> must require that for an extended period of time, and the patient must
> be able to tolerate and require 12 mg minimum of hydromorphone.
>
> \[Slide\]
>
> The boxed warning goes further to say that Palladone capsules are not
> intended to be used on an as needed basis or as the first opioid
> product prescribed for a patient.
>
> Palladone capsules are only for use in opioid-tolerant patients.
> Therefore, they cannot be the first opioid product prescribed for a
> patient. Use in non-opioid-tolerant patients may lead to fatal
> respiratory depression. This is very clear, right up front.
>
> We also go on to state that Palladone capsules contain an opioid
> agonist that is a Schedule II controlled substance with high potential
> for abuse, similar to morphine, oxycodone, oxymorphone, fentanyl and
> methadone. In addition, the high drug content in the extended-release
> formulation may add to the risk of adverse outcomes from abuse.
>
> \[Slide\]
>
> We then go on to tell the prescriber or dispenser that Palladone can
> be abused in a manner similar to other opioid agonists, legal or
> illicit. This should be considered when prescribing or dispensing
> Palladone in situations where the physician or pharmacist is concerned
> about increased risk of misuse, abuse or diversion.
>
> Lastly, the admonition against compromising the delivery system,
> taking chewed, dissolved, or crushed Palladone capsules or its
> contents can lead to the rapid release and absorption of a potentially
> fatal dose of hydromorphone.
>
> \[Slide\]
>
> In the indications and usage section we reiterate the fact that it is
> not to be used as a first opioid or on a p.r.n. basis and we emphasize
> the need for physicians to individualize therapy in every single case.
>
> \[Slide\]
>
> Let\'s talk briefly about the messages in the proposed patient package
> insert. Again, the admonition about intentional or unintentional
> compromising of the formulation, keeping Palladone away from children
> to avoid unintentional exposures; letting patients know right up front
> that this is an opioid or narcotic pain medicine; letting them know
> that these are not for as needed use; and cautioning them to prevent
> against theft and misuse.
>
> \[Slide\]
>
> Our medical communications\--we have a single telephone number,
> staffed around the clock by trained healthcare professionals to
> provide product information for other healthcare professionals, to
> receive adverse event information and put that into our
> pharmacovigilance system, and to address product inquiries and
> complaints.
>
> \[Slide\]
>
> Let\'s talk about the promotion. We have had discussions with various
> groups and individuals and we have decided that we would launch
> Palladone in a phased manner. It will initially be promoted by a
> subset of the sales force to a limited group of healthcare
> professionals for approximately four months. During that time there
> will be an ongoing evaluation of promotional message retention and
> understanding by healthcare professionals by an independent third
> party that we will contract with. Based on what we find from that, the
> introduction of the drug will gradually be expanded based on that
> experience and any modifications that derive from that experience.
>
> \[Slide\]
>
> What will we be looking for? We will be looking for the evaluation of
> messages; understanding patient selection criteria, did the
> practitioner get who is an appropriate candidate for Palladone or not?
> Understanding dosage and administration, did they understand this is
> not a p.r.n. drug; this is not the first opioid and things of that
> nature? Understanding what CII designation means and understanding how
> to recognize abuse and institute practices and procedures in their
> practice to minimize diversion.
>
> \[Slide\]
>
> In summary, our phased launch program, we believe, will help ensure
> that healthcare professionals understand our messages. It will enhance
> the quality of our promotional activities, and we believe that this
> current environment dictates that all future approvals for CII opioid
> analgesics should be launched in this manner.
>
> \[Slide\]
>
> I want to briefly go over a few examples of interventions that we have
> done of educational nature, community outreach nature and law
> enforcement support.
>
> \[Slide\]
>
> Healthcare practitioners learn by a variety of ways. Therefore, we
> have a variety of tools available to help them learn, including
> teleconferences and distance learning for the rural practitioner who
> may not be able to leave her practice to get to a CME event somewhere.
> We also circulate guidelines from the federation of state medical
> boards and from individual state medical boards in those states to
> help practitioners do a better job of complying with prevailing rules.
>
> \[Slide\]
>
> Here is an example of another intervention that we did. The need was
> this, practitioners were telling us \"I want to use urine testing in
> my practice to screen for illicit substances and also to ensure
> adherence to the treatment plan but, you know, this stuff is not in a
> textbook anywhere; it\'s not in one place.\" We made a grant to the
> California Academy of Family Practitioners. They put together family
> physicians; they put together a group of experts and assembled this
> monograph.
>
> What were the results of this? By request we have now distributed over
> 100,000 copies of this, not to mention the downloads from the
> California Academy\'s web site and this is, in fact, our most
> requested piece of enduring material. It has such pearls that one
> might not find in there that, for instance, hydromorphone is an active
> metabolite of hydrocodone. Many physicians don\'t know that in a
> clinical setting if you have a patient on hydrocodone and you order a
> GC mass spec of their urine and hydromorphone comes back you might
> misinterpret those results and think that they are being non-compliant
> when, in fact, you are giving them hydromorphone; you are giving it to
> them in the form of a hydrocodone.
>
> Likewise, in a medical examiner setting this is important because in a
> postmortem assay, if you get hydromorphone, you might attribute the
> death to hydromorphone when, in fact, hydrocodone was the cause.
>
> \[Slide\]
>
> Slide kits of lawful prescribing, what are the principles of lawful
> prescribing and how do you prevent diversion, a very popular thing.
> Here, again, with an external advisory board of experts we have
> produced over 10,000 of these.
>
> Then in our second edition, which is shown here and copies of these
> are available if you wish to receive them from the secretary of the
> committee, we revised it with images based on feedback from the
> physicians\--\"gee, I want to know what track marks actually look
> like.\" So, we now have pictures of track marks and skin-popping
> scars.
>
> \[Slide\]
>
> What was the need here? Mr. Joranson talked about this yesterday to
> some extent, a joint program with the National Association of Chain
> Drug Stores, NADD, National Association of Drug Diversion
> Investigators and the Pharmaceutical Security Institute where there is
> an internet clearinghouse where police officers and pharmacists can go
> and find out about pharmacy robberies one by one to compare MOs and
> patterns and, hopefully, spot the patterns and stop the perpetrators.
>
> \[Slide\]
>
> Tent cards with the DAMMADDs and MAAD moms against drug dealers. We
> have provided seed money for their web side, tent cards with a phone
> number and the URL that are placed in pharmacies. What are the results
> of this intervention? To date, 21 convictions of pharmacy robbers.
>
> \[Slide\]
>
> Law enforcement support, the need\--law enforcement said, \"gee if we
> stop someone on the street and we see a bunch of pills in the car we
> don\'t know if they\'re blood pressure pills or asthma pills or
> something they shouldn\'t have.\" So, we were approached by NADDI and
> we gave them a grant. They have now distributed over 100,000 of these
> photo ID cards, and Commander John Burke who, by way of disclosure, is
> a consultant for us, said \"these brochures were one of the hottest
> projects we\'ve ever done.\"
>
> \[Slide\]
>
> The need\--how to stop altered, forged and counterfeited
> prescriptions. The solution\--security paper. This paper has a number
> of security features, including \"void\" appearing, as you can see
> faintly here. It shows up better in real life; it doesn\'t project
> well but no matter what you have your scanner set on or your
> photocopies set on, you are going to get a line of \"void\" across
> there. It is also watermark paper. It is also sort of a water colored
> pattern like your checks so if you try to smudge or alter a
> prescription it will be very obvious. We have now been distributing
> these free of charge.
>
> The results of this\--a lot of physicians are using them and,
> secondly, a number of states have now recommended this to physicians.
> Some states are contemplating making it mandatory.
>
> \[Slide\]
>
> Public service ads, the Household Survey data and also alerting
> parents to the fact that, you know, kids find drugs in lots of places
> and the street is not the only place. Know what is in your medicine
> chest.
>
> \[Slide\]
>
> Communities that Care is a structured planning system that is based on
> 20-plus years of NIH-funded science research that provides strategic
> consultation; working with communities to provide an integrated
> approach to diminish these kinds of problem behaviors in communities.
> The reason is that research has shown that these are linked. If you
> just go after teen pregnancy and that is all you do, you are not
> likely going to make a dent if there is violence in the school, high
> dropouts, etc. Likewise for drug abuse. The CTC program which Michelle
> Ridge, Tom Ridge\'s wife is the national spokesperson for, is working
> with this and we are supporting this in a number of communities right
> now.
>
> \[Slide\]
>
> The need\--young people. The Household Survey data showed that the
> 12-17 demographic are the ones who are the most frequent new initiates
> of pain reliever non-medical use. Targeting middle school students,
> the strategy was to make these so-called \"tweens\" feel sorry for
> people who abuse prescription drugs because they have no self-respect
> and dignity. The key message is if you abuse prescription drugs you
> will lose your dignity; trying to resonate to what is important to
> this demographic, if you use drugs you are not cool anymore.
>
> \[Slide\]
>
> We have done it in a way that resonates, this sort of gross-out humor:
> \"picking your nose at lunch does not count as dessert\" and \"spastic
> shaking caused by prescription drug use is creepy\"\--painfully
> obvious is the conclusion, hence the tag line for the program. We have
> a web site. There have been over 300,000 hits on this web site and
> over 4,000 copies of this material downloaded in addition to the ones
> we have distributed in hard copy form.
>
> \[Slide\]
>
> Does this work? We are not really sure but there was last week, at the
> Household Survey press conference, an encouraging comment by John
> Walters, the current director of ONDCP, that said that the data
> suggest that youth who have heard anti-drug abuse messages have lower
> rates of abuse than those who have not heard the messages\--not a huge
> difference but if my kids are in the 11.3 percent, that is where I
> want them to be.
>
> \[Slide\]
>
> Multi-faceted surveillance, this is a key tenet of any risk management
> program. You have heard things about that.
>
> \[Slide\]
>
> Again, monitoring for patient safety, pharmacovigilance, including a
> structured, regular ongoing review of scientific literature;
> monitoring for other populations I mentioned; national surveys, as I
> have mentioned, the ones we have looked at and it is not passive
> monitoring, as I have shown you from the special data we have from the
> Household Survey; also monitoring the future. Some of our consultants
> met with the people who do monitoring in the future and actually got
> them to modify this high school-based survey to include issues about
> prescription drug abuse and remove things that probably didn\'t have
> very high abuse prevalence, such as laudanum.
>
> Media surveillance\--we have an active sample through one of the
> clipping services where we look at media surveillance to find out if
> there are reports of abuse or diversion around the country.
>
> Then, the RADARS system. This is an evolving system but it is
> innovative. We are very excited about it. We think we have some very
> good data. Of course, we fine-tune as we go along, but I think it is
> something that you will find interesting and for that I would like to
> introduce my colleague, Dr. Schnoll.
>
> **RADARS Surveillance System**
>
> DR. SCHNOLL: Thank you very much.
>
> \[Slide\]
>
> I am going to be talking to you this morning about the RADARS system
> and I would like to reiterate something that Dr. Haddox said to you
> already, that this is an evolving system. As you heard yesterday from
> Dr. Winchell, there are no guideposts for how to run this type of
> surveillance; there are no data out there. We have some clues from
> research that has been done in the surveillance of altram and Meridia
> but we felt we had to expand this system. You will be seeing some data
> today that were sent to the FDA but they have not had the opportunity
> to comment on those data at this time.
>
> \[Slide\]
>
> We had picked up the media indicating that OxyContin abuse was
> becoming a public health concern. We recognized that we did not have
> the expertise to deal with this on our own and so we put together a
> panel of outside experts to assist us in dealing with this situation.
> This external panel, the external advisory board, was formed in June
> of 2001, and part of what they did was to review existing databases.
> They recognized from these reviews that the data in these databases
> was often not timely, being published or presented sometimes a year or
> more after the data had been collected, and the data were not
> necessarily geographically specific. What we were hearing and seeing
> was that the problems of prescription drug abuse were not uniform
> nationally but seemed to have specific target areas around the
> country.
>
> So, the programs that were developed in RADARS were developed to
> provide geographically specific and timely data. The question came up
> yesterday about whether or not these data were presented to the FDA,
> and I would like to mention that on June 23 we had a meeting with the
> FDA to present RADARS data and the FDA, and other federal agencies, do
> meet with the external advisory board on a quarterly basis to review
> what is happening with the RADARS system.
>
> \[Slide\]
>
> These are the members of our external advisory board. As you can see,
> there are many well-known researchers in addiction, people who are in
> policy positions regarding prescription programs and law enforcement.
>
> \[Slide\]
>
> The goals of the RADARS system are primarily to study the nature and
> extent of abuse and diversion of scheduled prescription opioids, and
> you see the drugs that we are studying here. These are major and
> important Schedule II and III prescription opioids. In addition, the
> goal of the external advisory board and the RADARS system is to
> develop and suggest to Purdue interventions to reduce both diversion
> and abuse.
>
> \[Slide\]
>
> The objectives are to proactively collect timely and geographically
> specific data on the abuse and diversion of the drugs you have
> previously seen.
>
> In addition, as has come up here already by Dr. Strom this morning,
> there is a need to develop rates and we need to develop these rates
> both on a national and a local level because, as I mentioned, problems
> do not exist uniformly across the United States.
>
> In addition, we have to develop interventions and these interventions
> are suggested at times by the EAB and are done in collaboration with
> Purdue to reduce the diversion and to monitor the outcomes of these
> interventions.
>
> In addition, we review existing databases, such as you have seen with
> the National Survey of Drug Use and Health, to do some other analyses
> of these databases and review the literature to look at new data as
> they are emerging. We see what we are doing with RADARS as
> complementary to these existing programs.
>
> \[Slide\]
>
> There are several levels of activity involved in the RADARS system.
> Signal detection is the first one we do, and I am going to go over
> some of the data from our signal detection systems.
>
> From signal detection the data are then taken and merged and they are
> sent to the Johns Hopkins University where relative rate
> determinations are done, and I will discuss that a little further
> later on.
>
> When we receive a signal that we feel is at a level that requires
> something to be done, we go in and investigate that signal and do
> verification as to what that signal means. We may get data from other
> sources at Purdue which will launch a signal verification.
>
> The three bottom items, the focused studies, interventions and
> outcomes, will depend on what happens with that signal verification
> and so don\'t always occur.
>
> \[Slide\]
>
> The signal detection component functions as an early warning system.
> As I have mentioned already, the data are timely and you will see that
> as we already have second quarter data from 2003. They are
> geographically sensitive and we can break the data down to the first
> three digits of the zip code. This makes it very useful for monitoring
> localized outbreaks of an event that may occur with a newly approved
> drug. The threshold we have set for signal verification is five or
> greater cases per 100,000 population in that three-digit zip code. We
> feel that that is a very sensitive level and this may be from a single
> detection study or from a combination of all of the signal detection
> studies.
>
> \[Slide\]
>
> The signal detection studies are funded by Purdue. The studies, as you
> will see, are conducted at major universities under the direction of a
> principal investigator, and the data are independently housed at those
> universities and reported to the external advisory board and Purdue on
> a quarterly basis.
>
> \[Slide\]
>
> Through the signal detection studies we have covered a wide area of
> the United States. If you look, there is the Key Informant study with
> the stars; our Drug Diversion Network, with the diamonds; and DENS
> Network, with the yellow circles and these are the states that are
> either wholly or partially covered by the Poison Control study. So, we
> have a rather significant area of the United States covered with these
> studies.
>
> \[Slide\]
>
> The principal investigator for the Key Informant Network is Dr. Ted
> Cicero who is with us today. The key informants are made up of pain
> specialists, NIDA grantees, drug abuse specialists and others who can
> provide information to us in their local area about what is going on.
> We have picked one three-digit zip code to present some data to you to
> show the kind of data that we can collect.
>
> \[Slide\]
>
> As you will see, the data cover a range of drugs and I think it is
> important to point out that this is a very sensitive system and we are
> able to detect already abuse of buprenorphine, a drug that does not
> have a lot of prescriptions at this time. But we can see changes over
> time in what is happening with the various drugs on which we are
> collecting data.
>
> \[Slide\]
>
> The law enforcement drug diversion signal detection study is under the
> direction of Dr. James Inciardi, at the University of Delaware, and he
> is collecting data from drug diversion units around the United States.
> As you can see, we are continually trying to increase the number of
> key informants and units from which we are collecting information.
>
> \[Slide\]
>
> These are the sites that have responded in each quarter. These are the
> number of cases that they are reporting. We have consistent response
> from about 85 of these sites each quarter, and there is a group of
> about 85-90 key informants who respond to us each quarter.
>
> \[Slide\]
>
> In each of those cases there may be several drugs mentioned. Here is
> the data from the four quarters of 2002 and up to 2003 second quarter,
> and you can see there is wide variation in the diversion of different
> prescription drugs, and we have some benzodiazepines included here.
> Hydrocodone is the most commonly reported. OxyContin, which is
> separated from other oxycodone products, appears to be dropping a
> little bit over this time but, as has been reported in the press, we
> are beginning to see some increase in methadone mentions.
>
> \[Slide\]
>
> Yesterday you heard Dr. Winchell mention the Drug Evaluation Network
> System that is under the direction of Dr. Tom McLellan at the
> University of Pennsylvania. The important part of this system is that
> it collects data on a real-time basis. In some of the other systems
> you have heard about the data are collected, say, once a year and then
> the report may not occur for some time.
>
> \[Slide\]
>
> These are data on 11,000 consecutive admissions to the programs in the
> DENS system. There are about 80 programs nationally, some in urban
> areas and some in rural areas. As you can see, again hydrocodone is
> the most frequently mentioned drug. There are specific questions asked
> about these drugs in the DENS interview, and hydromorphone is also
> picked up.
>
> \[Slide\]
>
> As you see again, we can plot over time what is going on with these
> drugs. This is lifetime reported use of hydromorphone and this is past
> 30-day use, as Dr. Haddox mentioned, which is a surrogate for recent
> current use. I would like to point out the scale here. This only goes
> up to 3.0 so this is not a major rise in the problem.
>
> \[Slide\]
>
> We are also collecting data from poison control centers. One of the
> most important things about the data from the poison control centers
> is the fact that the people who are collecting the data give very
> specific information about what the tablet is. They ask about what the
> markings are on the tablet, the size, the shape, and they can then
> look at a book that gives them specific information and say precisely
> what branded or unbranded drug was being reported.
>
> \[Slide\]
>
> This is a map showing, in our pilot study, the coverage we have from
> the poison control system. It covers over 25 percent of the United
> States and, as you can see, covers some of the states mentioned
> yesterday as areas with high problems, Kentucky, Virginia, Maine, and
> we are trying to expand this system gradually to include more of the
> United States.
>
> \[Slide\]
>
> There are two types of calls that come in to the poison control
> centers. One is an information call where somebody may have forgotten
> what their pills are. As you know, many people will put all their
> pills into one little box and then they can\'t remember so they may
> call to find out what a specific pill is, or somebody found a pill.
> But the ones we are most interested in are the intentional exposure
> calls. These are the calls when somebody has taken a drug either for
> abuse problems or for suicide.
>
> As you can see, these are data from all of the poison control centers
> from which we collect data combined and we have worked at a rate per
> 100,000 based on the population covered by those centers. Again, you
> can see hydrocodone here, oxycodone\--this does not include OxyContin
> which is covered separately\--and the other drugs involved.
>
> \[Slide\]
>
> Now, the data that are collected from these signal detection studies
> are then sent to Washington University where we have a central
> database housing all these data. The data are collated and then
> specific data fields are sent to Johns Hopkins University where rates
> are calculated.
>
> Now, as I mentioned earlier and Dr. Strom has brought up, the
> denominators are very important in calculating these rates. In looking
> at this, it is clear that there is not one simple denominator to use
> to provide us with the information we need. If you are going to look
> at patients you have to look at patient day exposure. A short-acting
> opioid may only be used for 10, 11 days. An extended-release opioid,
> such as OxyContin, may be used for 24 days so you have more exposure
> and you may have a higher dose.
>
> You also need to know how much drug is out there, kilograms sold. If
> you are just looking at prescriptions you may get data that are biased
> because IMS data provides prescriptions mainly from retail pharmacies
> and currently, for a drug like hydromorphone, there is a significant
> portion of that drug that is being dispensed in hospitals and
> long-term care facilities those are not included in the IMS data. So,
> unless you are aware of that you can get a skewed rate so there are
> many different types of denominators that we have to look at to find
> out which is the most appropriate to provide us the information that
> we need.
>
> Using these denominators we are trying to calculate relative rates of
> abuse and diversion of the drugs that we are investigating, and with
> this we can compare one drug to another and compare a drug to itself
> over time to look at changes in the rates.
>
> \[Slide\]
>
> To give you an example, we have looked at DAWN data and created a rate
> based on total kilograms sold. This is not just the kilograms
> dispensed in retail pharmacies but the total kilograms including
> hospital and other sources. As you can see, there is some consistency
> of those rates. OxyContin has gone up. This is morphine, in the
> purple. We do not have the 2002 OxyContin data yet since the DAWN data
> were just released and we have to obtain the specific data from SAMHSA
> to get that.
>
> \[Slide\]
>
> Once we pick up a signal, as I mentioned five or greater cases per
> 100,000 population in a three-digit zip code, we have our field
> researchers go in using a questionnaire that is structured to try to
> verify the nature of that signal. This is very important because we
> are finding that there are different problems going on in different
> parts of the country. We have recently investigated a problem in a
> tribe of native Americans in the northwestern part of the United
> States where the problem appeared to be drug being smuggled in from
> Canada. In another part of the country we found that it was a city,
> 20,000 people, a lot of nursing homes and assisted living facilities
> and 18 pharmacies for 20,000 people. In a third area we discovered
> that river boat gambling had moved into the area and brought in a lot
> of outsiders who were using drugs.
>
> If you look at these differences, it tells you that there is not one
> single approach that can be applied on a national basis for these
> various problems, and that is why we need geographic specificity in
> terms of what we are doing. As mentioned here, the results of these
> interviews are presented to the EAB for suggestions on where to go.
>
> \[Slide\]
>
> I mentioned the focused studies. We have two focused studies that are
> currently going on, one in southwestern Virginia under the direction
> of Dr. Janet Knisely at Virginia Commonwealth University, one in Maine
> under the direction of Dr. Heimer at Yale University, and we are soon
> to implement a third in eastern Kentucky under the direction of Dr.
> Carl Leukefeld at the University of Kentucky.
>
> So far, information from these studies has pointed out that, one, it
> is very difficult to collect data from people in rural areas. They are
> very reluctant to talk to outsiders who come in to try to gather
> information from them. But we are also discovering that prescription
> drug abuse has been endemic in these areas for a long time and people
> go from one drug to another. So, we are getting some very important
> information.
>
> \[Slide\]
>
> Based on the information we get, we will be developing, in conjunction
> with the external advisory board, interventions that are specific to
> the area. In one case we found a physician who was performing some
> illegal activities and that was reported to the local authorities. As
> I mentioned, the interventions are specific. Dr. Haddox has gone over
> some of the interventions that the company is already doing.
>
> We need to look at outcomes for these interventions, and we will
> monitor carefully with our signal detection studies to see if there is
> a change but we will also look at other indicators.
>
> \[Slide\]
>
> So far, we have learned something about prescription drug abuse from
> the RADARS system. One, that abusers of a given opioid drug are
> similar to abusers of other prescription opioids. There seems to be no
> specificity in terms of the abusers. These individuals are typically
> individuals who have abused other prescription drugs as well as
> illicit drugs. This is not a problem of ethnic minorities and, as
> mentioned, the problem seems to be endemic in some of these areas.
>
> \[Slide\]
>
> We feel, in summary, that the RADARS system establishes a standard for
> proactive collection of data on abuse and diversion and provides
> relative rates of abuse and diversion for the drugs of interest. We
> are able to detect abuse and diversion of the drugs that are
> infrequently prescribed, as pointed out by buprenorphine, and the data
> are generated in a geographically specific area and in a timely
> fashion.
>
> I would like to now turn the microphone over to Dr. Herbert Kleber.
>
> **Prescription Drug Abuse**
>
> DR. KLEBER: Thank you for the opportunity to meet with the committee
> today.
>
> \[Slide\]
>
> I would first like to point out this is not a new problem.
> Prescription drug abuse has been with us for a very, very long time.
> The under-treatment of pain has been with us for a very, very long
> time and the question is always the tension between these areas. How
> do we keep effective pain relievers available for appropriate medical
> use while decreasing abuse? If I stood up here and said we have the
> answer I think you would all get up and walk out, and rightfully so.
> This is an evolving area. There is no one answer yet. We are improving
> what we do; we don\'t have the answer.
>
> \[Slide\]
>
> At the turn of the century we had an enormous problem with patent
> medicines. They were often unlabeled. One of the favorites was Mother
> Winslow\'s Soothing Syrup which was rubbed on the gums of teething
> babies and also taken by the mothers when they had trouble dealing
> with the teething babies. Finally we had the Pure Food and Drug Act in
> 1906 which at least required that these patent medicines be labeled as
> to ingredients. It certainly did some good. On the other hand, it left
> a lot of openings. You still had doctors and pharmacists who were
> basically willing to sell these medications to whoever wanted them,
> and you had mail order catalogs. So, there is really nothing new under
> the sun, today we have the Internet drug sales; in those days you had
> mail order catalogs.
>
> Then, in 1914 the Harrison Act tried to close some of these loopholes
> and you needed prescriptions by physicians for reasonable treatment of
> pain. At the same time, as often happens with unintended consequences
> or maybe intended, basically between the Act and the Supreme Court
> interpretations, it ended the involvement of the general medical
> system in the treatment of addiction. It stayed that way really until
> methadone came along, and you will hear more about that from my
> colleague, Dr. Kreek, this afternoon.
>
> \[Slide\]
>
> The Harrison Act did not solve the problem of prescription drug abuse.
> We keep trying to do it by coordinating things better. The last bullet
> there, ONDCP, is one that you have heard. I had the honor to serve as
> the first deputy director, back in 1989, under Bill Bennet and the
> first President Bush.
>
> We keep trying to improve things, not just with coordination and with
> laws regulating prescribing, but with enforcement activities so the
> Bureau of Narcotics morphs into the Bureau of Narcotic and Dangerous
> Drugs, which morphs into the Drug Enforcement Administration. Each
> probably is somewhat of an improvement over what came before but is
> clearly still problematic.
>
> \[Slide\]
>
> Who are the abusers? I have been in the field for between 35 and 40
> years and it has been my experience that there are really four groups
> of people that we need to talk about. We need to talk about addicts.
> We need to talk about pain patients. We need to talk about addicts who
> have pain, and we need to talk about pain patients who become addicts.
> Each of these is a different category. They need to be approached as
> individuals, as is beginning to emerge from the discussions this
> morning, especially as Dr. Baxter pointed out that we need to keep in
> mind that there is no one approach that is going to work for all of
> these, but most non-medical users of prescription opioids are polydrug
> abusers. These are not people who just abuse these medications; they
> also tend to abuse alcohol, marijuana and other drugs. Most pain
> patients do not abuse these medications nor do they become addicts.
> There aren\'t as good studies as we would like, especially prospective
> studies, but most studies of the few that we have suggest that it is
> less than five percent of people who receive legitimate medications
> for pain end up addicted\--not dependent, a different term, but
> addicted.
>
> \[Slide\]
>
> Since the patient is not the key person at risk for prescription drug
> abuse, how much legitimate medical need needs to be tolerated to
> reduce abuse? Again, it is that tension that we have talked about that
> there is no easy answer to.
>
> \[Slide\]
>
> So, let me wrap it up in the next minute or two. Quick fixes do not
> work for complex problems. I wrote in an op ed in \"The Times\" 15
> years or so ago that we should leave the quick fixes to the addicts.
> There is no easy solution.
>
> There are often unintended consequences of good intentions. The
> concern over OxyContin led many physicians to stop prescribing it and
> many pharmacies put signs in their windows saying \"we don\'t
> prescribe OxyContin\" and it led, instead, to a marked increase in
> prescribing of methadone for pain relief and more diversion of
> methadone, which then has also the unintended consequence of casting
> disrepute on legitimate methadone maintenance programs.
>
> So, when you squeeze the balloon in one part it tends to pop out in
> another, often in areas where you don\'t expect it to. The patterns of
> drug abuse continually shift and preferences change. In the \'70s
> Quaaludes was a big problem and we haven\'t heard about that for quite
> a while. PCP was also a problem and this stayed with us.
>
> We continually search for technological fixes. One of my favorites was
> paregoric, which was camphor with a tincture of opium. The camphor was
> put in to deal with abuse. One of the first things my addicts taught
> me, when I was at Lexington treating patients there in the early
> \'60s, was you simply take the paregoric, put it in the freezer, the
> camphor freezes, the tincture of opium doesn\'t. You throw away
> anything that freezes, boil what is left and you now have opium. So,
> the addicts are very good at figuring out whatever system we come up
> with. Likewise, the Addiction Research Center which is now the
> intramural branch of NIDA, was really set up in the \'30s with one of
> its major missions to come up with a non-addicting analgesic, a strong
> analgesic, and we are still at it, guys. But, hopefully, maybe before
> the Red Sox beat the Yankees and win the pendant\--remember, I spent
> most of my years in New Haven so I am a Red Sox fan, not a Yankee fan.
>
> So we continue to search for technological fixes. We have certainly
> come up with better ones but I have great faith in the ability of true
> abusers to get around it. So, I expect evolutionary, not
> revolutionary, changes.
>
> \[Slide\]
>
> We have a number of strategies that have we have gone over. I am not
> going to reiterate them; you have heard about them. I have been
> associated with the RADARS program since its inception in July of
> \'01, and in my experience in treatment of addiction, treatment of
> pain, the risk management strategy that is used for OxyContin and
> Palladone and the RADARS part of that strategy is one of the most
> comprehensive I have ever encountered. Is it perfect? Absolutely not
> and that is why they have all these experts on the committee to try to
> keep tweaking it to improve it.
>
> \[Slide\]
>
> Secretary Thompson has just recently commented on the need for
> treatment. \"There is no other medical condition for which we would
> tolerate such huge numbers unable to obtain the treatment they need.\"
> Again, if many of these people who cycle through the system could get
> adequate treatment for their opioid problem there would be much less
> of a difficulty out there. With heroin, for example, less than 20
> percent of the individuals who need treatment are getting it.
>
> \[Slide\]
>
> Last slide, and this I think is a really important take-home message I
> want to leave you with, the past decade has witnessed the pendulum
> swinging toward adequate pain relief for patients. This has occurred
> under the impact of legislation, of lawsuits, of reports from learned
> societies. My own feeling\--hopefully I am wrong\--is that this
> pendulum swing is still very superficial; it is skin deep; it is easy
> to reverse and I think we need to pay attention to that, and it is
> important that any strategies that we come up with do not reverse the
> trend toward adequate pain relief for that segment of the population
> that needs it. Thank you.
>
> **Questions from the Committee**
>
> DR. KATZ: Let me thank the speakers from Purdue and from Columbia for
> their comprehensive presentations. Of course, it is always tantalizing
> because there are so many issues that we would all like to discuss in
> depth and we never seem to be able to satisfy ourselves there, but I
> am sure people around the table have questions for the sponsors and we
> have 15 minutes allocated for that. So, why don\'t we go ahead and
> take that. Dr. Dworkin first?
>
> DR. DWORKIN: I think this is a question for you, David. It seems to
> me, in thinking about risk management programs, that the extent of how
> widely the drug will be used is a consideration so that a risk
> management program for buprenorphine or transmucosal fentanyl might
> need to be different than for more widely used drugs like OxyContin.
>
> So, I guess I would like to know\--and I hope this is not an unfair
> question\--by any measure OxyContin is a block-buster drug. looking
> down the road four or five years from now, how does Purdue view
> Palladone? Is it going to be another block-buster drug like OxyContin
> or do you view Palladone as being a more niche-limited used drug?
> There must be projections of this that your marketing projections have
> done.
>
> DR. HADDOX: There are marketing projections but we don\'t discuss
> commercial information in public, but let me see if I can answer your
> question in a way that satisfies the need. If you look at the
> indication for OxyContin and indication for Palladone, they are fairly
> similar with the exception of that fourth test, that is, the
> opioid-tolerant individual who needs and requires 12 mg minimum of
> hydromorphone. So the estimation would be, I think logically, that it
> is going to be a smaller subset of patients than those who are taking
> OxyContin. Now, there are some five million patients in the entire
> country who might be appropriate candidates for opioids that are high
> potency. So, you know, OxyContin has a share of that. Maybe about 1.7
> million patients in a given year have been exposed to OxyContin. My
> guess is that Palladone will be smaller than that, but I really can\'t
> give you a scale of marketing projections.
>
> DR. KATZ: Dr. Crawford?
>
> DR. CRAWFORD: Thank you, Mr. Chairman. Dr. Haddox, thank you for the
> presentation. I have three very quick questions, at least there could
> be very quick answers.
>
> First, slide 30 with the boxed warning part of the indication states
> use for an extended period of time which, of course, could be subject
> to interpretation. What is the intent of the sponsor?
>
> DR. HADDOX: Well, this is a claim originally negotiated with the
> agency. It requires clinical judgment. Certainly, it is not
> appropriate for a day or two but it might be appropriate if the pain
> is going to last for a few weeks. It is somewhere in that range and we
> and the agency I think agreed, certainly with the labeling for
> OxyContin, that you don\'t want to, you know, draw a line in sand. You
> want clinicians to use their judgment and individualize therapy.
>
> DR. CRAWFORD: Thank you. The second one, slide 32, the capital letters
> with the boxed statement not to compromise the formulation, one thing
> that is very important in my opinion for us to understand is can you
> describe and quantify the potential or the likelihood of adverse
> effects if the formulation is compromised, as well as what the
> appropriate use is because we didn\'t see any figures on fatalities or
> other serious adverse events that may occur with the formulation?
>
> DR. HADDOX: I think you asked two questions there.
>
> DR. CRAWFORD: That was my second question. Can you describe and
> quantify what are the adverse effects, what is the likelihood of that
> occurrence if the formulation is used appropriately and if it is
> compromised?
>
> DR. HADDOX: That is what I meant by two questions, two conditions. If
> the formulation is used appropriately the safety profile in all of our
> studies we submitted to the agency is comparable to the safety profile
> of any other opioid. We, obviously, don\'t try to compromise the
> delivery system and give it to people and see what happens. So, we can
> only guess that it would be what the warning describes, which is why
> we and the agency agreed to put that in the proposed label.
>
> DR. CRAWFORD: Okay, and the last very quick question, the
> tamper-resistant pads, do they come preprinted with the product name
> or indication to the prescribers?
>
> DR. HADDOX: All they come preprinted with is the prescriber\'s
> information they would normally print\--name, address, that sort of
> stuff. In fact, we actually encourage prescribers, based on advice
> from law enforcement, not to preprint their DEA registration number
> either. So, you know, just your name, your phone number, your address,
> what you would normally do. Then, because they are distributed in
> different states, the vendor goes to the state board pharmacy with a
> prototype and says does this meet your requirements for prescription
> in this state? And, we have had to tweak that a few times so that it
> would be state specific.
>
> DR. KATZ: Dr. Ciraulo is next.
>
> DR. CIRAULO: Dr. Crawford asked one of my questions but I just would
> like to expand on that. Do you have data on how easy it is to
> compromise the formulation to make it from a modified release to an
> immediate release? Do you have PK data or toxicity data either in
> animals or humans that would give us some information on what we could
> predict might happen if it is easy to chew and get this into the brain
> more quickly?
>
> DR. HADDOX: There has been some work done on that. We don\'t do this
> in normal volunteers, as you might imagine. It is harder than some and
> it is not impossible but, again, being a public hearing here, I don\'t
> think it is prudent for public health to discuss ways people might
> compromise the delivery system.
>
> DR. CIRAULO: Sure, but the FDA, you have that data?
>
> DR. KATZ: But, Dr. Ciraulo, is your question what would be the
> likelihood of harm to some sort of person, say an opioid-naive
> individual, should they be able to ingest a compromised dose or an
> immediate-release dose of whatever is in one of these Palladone pills?
>
> DR. CIRAULO: Yes, that is my concern.
>
> DR. KATZ: So, if someone, for example, were able to compromise the 12
> mg tablet, just to pick a dose, and ingest that, in opioid-naive
> people what is the likelihood of harm? That is your question?
>
> DR. CIRAULO: Yes.
>
> DR. KATZ: Are there answers to that?
>
> DR. HADDOX: Well, I think, you know, the likelihood of adverse events
> is pretty clear. Which adverse event would occur I am not certain. I
> am not aware of people who have done that, who have given 12 mg of
> IV-push of hydromorphone to opioid-naive volunteers to see what
> happens to them. Even where I trained you wouldn\'t get too many
> medical students to volunteer for that study. So, I think the warning
> is appropriate. It says what we all believe in my clinical experience,
> that if one were to compromise this, this is very risky behavior.
>
> DR. CIRAULO: I think my problem is I can\'t advise anybody\--I can\'t
> advise the agency without knowing the toxicity data, but you have it.
>
> DR. RAPPAPORT: We will have the data, we do have the data and are able
> to review that but to some extent Dr. Haddox is correct, we would
> expect certain severe adverse events to occur, but there is not a lot
> of clinical work you can do to study that.
>
> DR. CIRAULO: Yes, my concern is when this medication is on the street
> and gets diverted, as it will get diverted and as addicts begin to
> tamper with it, what are we going to face from a public health
> standpoint?
>
> DR. RAPPAPORT: Theoretically there could be people dying from taking
> these products and abusing them, but I don\'t know that we can say any
> more than that.
>
> DR. KATZ: Dr. Haddox, correct me if I am wrong, but it sounds like we
> should assume for the purposes of this discussion that the likelihood
> of harm for an opioid-naive individual ingesting an immediate-release
> formulation of any of these dosage forms of hydromorphone would be
> very high. Is that a fair assumption?
>
> DR. HADDOX: I think that is a fair assumption with any equivalent dose
> of hydromorphone, regardless of formulation.
>
> DR. KATZ: Dr. Aronson is next.
>
> DR. ARONSON: Thank you. I have a number of questions. Let me ask you,
> Mr. Chairman, if you wish for me to ask them all. Some are directed to
> Dr. Haddox and others are directed to some of our other speakers.
>
> DR. KATZ: Any questions to any of the sponsor representatives is fine.
>
> DR. ARONSON: Okay. This is an operational question that I would like
> to direct to you, Dr. Haddox. You mentioned a number of risk
> management tools that you are going to launch or implement as you
> phase your launch of Palladone. Other than just telling us that there
> are guidelines and brochures and CDs, etc. that you wish to promote in
> an educational process, what is the metric that you are going to use
> to judge whether or not that message was received, and what is the
> threshold that you would use to determine whether or not you are going
> to accelerate your launch beyond your first phase?
>
> DR. HADDOX: Let me answer that in two parts. Number one, it is clear,
> as I said before, that there are some elements of this that are
> Palladone specific\--the phased launch, the labeling for Palladone,
> etc. But the big difference between Palladone and OxyContin is that
> all of these things that I have talked about, except for the phased
> launch which hasn\'t occurred yet, are already in place. Practitioners
> have gotten the tamper-resistant pads. They have been educated on
> abuse and diversion. Those things are out there.
>
> RADARS is up and running and that is the second part of the answer. I
> believe that one of the major mechanisms we will use in the evaluation
> of the message will be those four points that I talked about. The
> threshold is still being determined because it is an evolutionary
> process. We are still trying to sort out how to do that best. But the
> big metric will be will RADARS pick up something early on and allow us
> to do targeted interventions to try and suppress the issue.
>
> DR. KATZ: Does that answer your question?
>
> DR. ARONSON: I think so. I think the point is, is there a threshold
> whereby you would just sort of delay or stop your process of evolving
> the launch?
>
> DR. HADDOX: I think it would be premature for us to try and determine
> threshold until we try and get some data back from that message
> evaluation to see what it looks like. I think at that point we will
> get a sense of what should be the cut-off or what we should do
> differently.
>
> DR. ARONSON: The segue to that\--and I would firstly say that the
> RADARS program, in my opinion, is responsible and you ought to be
> commended for the effort, but as was pointed out by this committee,
> the problem of clearly defining the denominator still persists despite
> your best efforts and so I raise the question is more incomplete data
> better than complete data? I suppose we are having to confront that.
>
> The part of this equation that I think we need to consider, and I am
> asking if you have attempted to do that, is the mirror graph, if you
> will, the decrease in the number of patients that need to be treated
> for pain. As that decreases, as that tendency would drop we would
> expect the adverse mirror curve to increase, and at one point do the
> lines cross and is that the point that we find acceptable? Is there
> any data to show the benefit, improvement?
>
> DR. KATZ: Can you clarify that question?
>
> DR. ARONSON: I will try. We conceptually appreciate that the reason we
> would consider, if you will, approving another drug is because we wish
> to do good for those people who deserve to have good done. Are we
> measuring the impact of how much good we are doing and comparing that
> to the potential harm that may come of it? We have only seen the
> absolute increase in harm but we haven\'t looked at that in a
> comparative way to the absolute good that we have done. Are there any
> data to show that?
>
> DR. HADDOX: Well, as I have said before, if you look at survey data,
> survey data have not really changed substantially in the past 15 years
> in terms of the prevalence of under-treated pain. I think, however,
> that the denominator issue that you raised in the preamble is
> important because, as Dr. Schnoll pointed out, we don\'t anticipate a
> single denominator. We think that this is a complex issue and to
> really understand this we may have to look at multiple denominators,
> some of the ones that he pointed out, so that we can look at what is
> the relative risk of abuse or diversion of one formulation to another,
> those sorts of questions. It still begs the question how can we
> measure the benefit to the populace and that is a tough question.
> Outside of survey methodology, I don\'t have any suggestions right now
> but I would be willing to entertain them.
>
> DR. KATZ: I want to make sure we are getting to the core of your
> question. Are you suggesting that a risk management program such as
> the one that is being proposed for Palladone should incorporate a
> component that measures the societal benefits of the approach as well
> as the risks so that we can have a complete picture? Is that your
> question?
>
> DR. ARONSON: Absolutely. What we are confronted with is a balance of
> most good for least harm, and we need to have that side of the
> equation in order to make that decision and I do not see that side of
> the equation. So, yes indeed, I am asking that.
>
> DR. KATZ: And how would you suggest that be done?
>
> DR. ARONSON: Give me a moment.
>
> \[Laughter\]
>
> DR. KATZ: There is a long list; I will put you at the bottom so you
> will have some time. Dr. Cush, you are next.
>
> DR. CUSH: I have two questions, one for Dr. Rappaport or the agency.
> Could you just generally state what your requirements for
> manufacturers as far as pharmacovigilance are and what you want them
> to do in their program? Some of the agency requirements for
> pharmacovigilance for a product like this?
>
> The second part is going to be to Dr. Haddox. Could you tell us why
> you chose four months and to what selected health professionals will
> you be targeting initially, and is that the appropriate population,
> meaning is that the population that has also been shown to be guilty
> of improper use of these agents in the past?
>
> DR. KATZ: So, first question first.
>
> DR. TRONTELL: I will comment first on the regulatory requirements for
> pharmacovigilance. The regulatory requirements in that arena are
> uniform across all products and require reporting to the agency of
> adverse events that come to the attention to the sponsor
> spontaneously. They are mandated to send those to the agency and those
> in a certain category deemed serious by regulatory definition are, in
> fact, required to be sent to the agency on an expedited basis. I will
> defer now to Dr. Rappaport to talk about this particular class of
> drugs.
>
> DR. RAPPAPORT: We have been asking for some extra pharmacovigilance
> with this group of drugs, asking for expedited reports that are
> expedited on a faster basis, and following carefully indications of
> abuse, overdose and such. So, we are doing a little bit extra here but
> the general requirements are what we follow for all drugs in all areas
> of safety.
>
> DR. CUSH: So, is this risk management program we are talking about
> here part of the pharmacovigilance effort?
>
> DR. RAPPAPORT: Yes.
>
> DR. KATZ: The second question was on the specialists that are being
> targeted in the initial phase.
>
> DR. HADDOX: The intent is to have that portion of the sales force
> which calls on physicians who are likely to have patients for which
> Palladone would be an appropriate option. So, people like
> anesthesiologists, pain specialists, oncologists, that is the intent.
>
> As far as the four months, we had to start somewhere. We just decided
> we would collect the information. We will be looking at it as it comes
> in but four months is where we will sit down and really try and make a
> decision point.
>
> DR. KATZ: Next was Dr. Shafer.
>
> DR. SHAFER: Thank you. Three questions. I think they will all be
> pretty straightforward. The first is a simple pharmacokinetic
> question. In looking at the data on drug administration over the first
> 24 hours the peak concentrations are reached at 24 hours, suggesting
> you have done a very good job on the sustained release part. But that
> also suggests that over the first week of therapy there is the
> potential\--not a potential, the drug will accumulate until you reach
> your steady state. How much more does the drug level rise over the
> first week of therapy until you reach steady state?
>
> DR. HADDOX: Two to three days to reach steady state.
>
> DR. SHAFER: And how much has it risen? Has it doubled over that period
> of time?
>
> DR. HADDOX: No, I don\'t think so. Let me ask my clinical experts
> here.
>
> DR. KATZ: Could you come up to the microphone, please?
>
> DR. SHAFER: I was impressed that the peak was reached at 24, which
> means that you are then adding your next dose on top of that.
>
> DR. APFEL: David, if you could go back to the slide showing the steady
> state?
>
> DR. SHAFER: But we are really talking about the rise to steady state,
> not the steady state exactly.
>
> DR. APFEL: My name is Dr. Stuart Apfel.
>
> \[Slide\]
>
> DR. SHAFER: That shows the rise and what I am referring is the peak at
> 24. So, the question is how much accumulation will you get on top of
> that over the first week of therapy?
>
> DR. APFEL: We see that the levels continue to remain pretty much at
> that same level with continued exposure. As the drug is continued to
> be administered, once it reaches steady state the levels of the drug
> in the serum remain approximately the same. You can see it a little
> bit better here where you see very little variation.
>
> DR. KATZ: I think the question was what is the ratio of the blood
> level at day three to the blood level at day one. Is that right?
>
> DR. SHAFER: That is right. If we could go back because it is not in
> the handout that we received. The question is how much higher is this
> than the level at the end of the first day of treatment.
>
> DR. HADDOX: That is why I went back to this. There is the metric,
> right there. It is a little less than 2 ng/ml with a 12 mg capsule.
>
> DR. KATZ: But this is a 24-hour slide.
>
> DR. HADDOX: This is steady state. This is steady state and I am going
> to go back to the single dose to answer the question.
>
> DR. SHAFER: Let\'s go back to the single dose if it is the same dose.
>
> DR. HADDOX: The single dose was actually twice as high I believe.
>
> \[Slide\]
>
> This is 24 mg and there is the 2 ng/ml.
>
> DR. SHAFER: So it is approximately doubling.
>
> DR. GOLDENHEIM: Paul Goldenheim, Purdue Pharma. I think the answer to
> your question is it is a little bit less but we will get the precise
> answer for you, but steady state is achieved after two to three doses.
>
> DR. SHAFER: I have two other questions, quickly. One is, the question
> was posed yesterday to what extent is theft and criminal activity
> versus diversion from patient activity responsible for the misuse of
> drugs and diversion to addicts, and has your RADARS system been able
> to give us more information? We did not learn an answer yesterday when
> I posed that question. Have you learned anything from your RADARS
> system?
>
> DR. HADDOX: Well, certainly, the diversion study is showing what the
> police are intercepting either in undercover buys or busts. So, that
> is some idea of what is on the street. It does not tell us necessarily
> how it gets to the street. There are people who are feigning to be
> patients, who are scamming physicians. There are people who just take
> the easy way; don\'t have to worry about learning new symptoms to fake
> or getting fake medical records, they just go in with a gun or, you
> know, roll the place at night. No one is quite sure that the DEA does
> collect that theft and loss data and does categorize it, and I believe
> Dr. Willis made some reference to that in her presentation yesterday
> but those data reside at the DEA.
>
> Even so, that only gives you one piece of the question that you asked.
> That might give you a sense of what is from theft and loss, and that
> sort of thing, but it doesn\'t say what the doctor shopper, who in
> fact is not a patient, is getting on the street, or particularly,, the
> bad doctor who is indiscriminate and doesn\'t really care who they are
> writing prescriptions for.
>
> DR. KATZ: Dr. Schnoll, do you have a follow-up?
>
> DR. SCHNOLL: Yes, we don\'t have at this point specific information to
> directly answer that question. Most of the abusers get the drug from
> the street. I think your question is how does it get to the street.
>
> DR. SHAFER: Exactly.
>
> DR. SCHNOLL: That is something we are trying to investigate. There are
> many sources and, hopefully, as the RADARS system matures we will be
> able to provide that answer but I don\'t think anyone knows
> specifically where all the drug is coming from that gets to the
> street.
>
> DR. SHAFER: Do we even know if it is 1:10 versus 10:1?
>
> DR. SCHNOLL: No.
>
> DR. KATZ: Can you, Dr. Shafer, tell us why you think that is important
> in terms of developing a rational risk management program?
>
> DR. SHAFER: Sure, because part of the purpose of the risk management
> program is the concern about drying up the supply of drug to addicts.
> If that supply is entirely coming from criminal activity and is not
> coming from doctor/patient activity, or even if 98 percent of it is
> coming from criminal activity, not doctor/patient activity, that means
> the ability of these surveillance programs to impact that is going to
> be almost zero.
>
> DR. KATZ: Maybe it would be helpful to hear more information on what
> specific elements of the RADARS program are designed to yield an
> answer to that question.
>
> DR. SCHNOLL: Certainly the drug diversion part of the program is
> trying to do that, but also as we do our field investigations the
> field researchers go into an area and, if possible, try to interview
> users, abusers in the area to get information about the source of
> their drug. They also check with other people, local police, people in
> treatment programs to get that information. As of this time, we don\'t
> have sufficient data to put together the types of ratios you would
> like and, hopefully, we will be able to get that in the future.
>
> DR. SHAFER: How many abusers say I actually got this by scamming my
> doctor?
>
> DR. SCHNOLL: Not many.
>
> DR. SHAFER: Any?
>
> DR. SCHNOLL: Yes, some do. Some do but it isn\'t that many. When we
> ask the question, as I mentioned, what they say is, \"I got it on the
> street.\" How did the drug get to the street? I don\'t know.
>
> DR. KATZ: As I indicated yesterday, there are many issues that we
> don\'t have answers on and perhaps one of the things we could
> accomplish is not so much to give answers in the absence of data but
> at least to indicate what sorts of data are likely to lead to the
> right answers. Is that the sort of data that, in your view, would at
> some point in time, when it becomes available, give you the answers
> that you need?
>
> DR. SHAFER: Absolutely. Not only do drugs have risk/benefit ratios but
> programs, like surveillance programs, have, you know, cost/benefit
> ratios. And, without knowing that information, it is hard to assess
> whether the program is doing anything, whether it is really
> worthwhile.
>
> One other quick question, can you give me any examples from your
> RADARS program of how you have changed the marketing or promotion of
> OxyContin based upon the feedback that you got from the program?
>
> DR. SHAFER: Well, one of the things we would do, we would gather
> information, say, about someone in an area who was inappropriately
> prescribing and needed more education. We would bring more education
> to that person to try to bring them up to date on proper prescribing.
> In fact, we have one instance where a physician was prescribing the
> drug inappropriately. We had some targeted education with that
> physician and he realized that there were a number of people in his
> practice who were trying to scam him and actually reduced the number
> of people to whom he was prescribing opioids by about 20 percent. So,
> there was a very effective outcome in that.
>
> DR. KATZ: Dr. Cicero?
>
> DR. CICERO: Yes, I am Ted Cicero, consultant for the company. I run
> the Key Informant study and I am also the custodian of all the central
> databases at Washington University. I think what your question was is
> are we going to be able to\--and I think if we can show that map again
> from Dr. Schnoll\--
>
> \[Slide\]
>
> \--are we going to be able to look in an area where we are getting
> reports of abuse, where is that coming from and also reports of
> diversion in those areas. You will see a lot of overlapping areas. We
> have identified right now at a very preliminary level about eight
> areas where we are seeing both diversion and high rates of abuse
> occurring. What we need to be doing at this juncture, and we are in
> the process of doing it as you see with the map you are seeing
> here\--we have many areas where there is extensive overlap of systems,
> the poison control; we have also the diversion sites; we have the Key
> Informant Network.
>
> For instance, I can speak to St. Louis, that is where my residence is,
> and we are getting reports both of abuse and diversion. Looking into
> this, it appears that the two are very closely associated. Lots of the
> abuse is coming off the street and appears to have been diverted in a
> criminal sort of way.
>
> Now, the question you are asking that we really can\'t answer is what
> percent of the street drug is coming from theft or coming from a
> physician. We don\'t really have a good enough feel for that now but
> the important thing I want to leave you with is that we have the power
> to be able to do it. I think by having these overlapping systems, the
> natural connection for us at this point is to say, okay, we have
> diversion in an area. Let\'s go in there and find out where that was
> being diverted to. Is it being shipped out of state? Is it at a local
> level? And the abusers themselves who say they got it off the street,
> did they in fact get it from that source? My hunch based on
> preliminary data is that there is going to be a very strong
> association between theft of a drug such as this and what actually
> appears on the street.
>
> DR. KATZ: Laura Nagel, would you care to add to that question?
>
> MS. NAGEL: Thank you. We share your frustration in trying to determine
> where out of the closed system of distribution the drugs are being
> diverted. What we tried to do in preparation for this presentation is
> pull our cases. The majority of them are criminal cases. What Dr.
> Willis said was that in 60 percent of our criminal cases the source of
> diversion was a physician or a pharmacist. The other 40 percent were
> drug thefts, doctor shoppers, people like that. We separated out the
> doctor shoppers because we perceive that that is a physician who is
> unwitting, that was duped and, in fact, wasn\'t necessarily criminally
> liable.
>
> So, we feel very strongly that although there are thefts, that if we
> can educate the physicians, if we can reach them whether it is in
> labeling, whether it is in some sort of restricted manner, if we can
> reach the practitioners and educate them on the respect for the drug
> and the appropriateness for prescribing for the right patients at the
> right time, the right people will get the drug. But we perceive from
> our investigations that the physicians are a large, large percentage
> of our point of diversion whether unwitting or criminal. Therefore, we
> feel very strongly and support the committee\'s efforts to reach them
> because we have to do everything we can and this is a huge part of the
> problem for us.
>
> DR. KATZ: Can I just ask a little bit about that? Do you have a feel
> for what proportion of the diversion that comes from the physician as
> a source is unwitting versus criminal?
>
> MS. NAGEL: No, I would be guessing but we tried to do that when we
> broke out doctor shoppers. We didn\'t necessarily identify those
> physicians in the category we call criminal. If we perceived that a
> good doctor shopper duped them, well, education is going to help that
> but we didn\'t feel it was criminal so we dropped them in the lower 40
> percent. But we still had 60 percent. Now, that is our cases; that is
> not the universe but it is the best data I can offer you, but 60
> percent of our cases were criminal for physicians and/or pharmacists.
>
> DR. KATZ: Thank you. Dr. Baxter you are next.
>
> DR. BAXTER: This is very excellent. I would like to commend you first
> on the presentation. It is very excellent that my opportunity to speak
> comes right now because it seems that the key step in risk management
> is the education of the physicians. In fact, the RADARS system itself
> is potentially going to be very excellent.
>
> But getting back to the point that Dr. Crawford made and some of my
> other colleagues, it is very important, once again, as you cited, that
> the appropriate patient is selected. Patient selection is going to be
> probably key in terms of managing the risk not only for Palladone but
> for OxyContin as well.
>
> It also goes back to what we previously discussed about the importance
> of assessing the risk of abuse because those individuals who are at
> high risk for abuse are probably not appropriate for selection unless
> there are certain precautions in place. I would wonder if it would be
> possible to add into that boxed warning that patients with high risk
> for abuse require additional monitoring. Now, what the additional
> monitoring is, that can be debated but I think that perhaps by adding
> that into the boxed warning that would cause physicians who are
> prescribing to at least become aware that there are other
> considerations when you are prescribing this medication and other
> opiates to high risk patients.
>
> DR. KATZ: Dr. Haddox, do you care to comment on that?
>
> DR. HADDOX: I am just trying to get back to the boxed warning here.
> Slide 30, 31 and 32.
>
> \[Slide\]
>
> I think that this may partially address your concern, the statement
> there is where we make it a point, with the agency\'s agreement, that
> this should be in the boxed warning. Now, if there are other things
> the agency wants to consider we are certainly going to interact with
> them in that regard but, to my reading, this addresses your point.
> Maybe I am not hearing it exactly right but it seems to me that it
> sets a fairly high cautionary note early on in the package insert, in
> the ads, and so forth, that this does have abuse potential and that
> this should be considered when prescribing or dispensing. I would
> assume then that those sorts of monitoring would be part of the
> consideration.
>
> DR. BAXTER: I wouldn\'t assume that. I think that if it is not said,
> then it hasn\'t been considered. So, to go a step further, I think
> that it would probably be very helpful in helping prescribing
> physicians, especially those primary care individuals who are not
> familiar with dealing with patients who have diseases of addiction. It
> will alert them that they need to first investigate if a person
> does\--at least ask the question because if you don\'t ask the
> question, you know, what the heck.
>
> DR. HADDOX: Let me respond in two ways to that, sir. I think now I
> have a better understanding of what you are talking about. We have a
> number of educational materials in different formats that strike at
> exactly that point of how to do an interview looking for risk factors
> for abuse or addiction. We have it in different ways so that a
> physician will get the message at different times depending on the
> materials to which they are exposed. As far as changing the label, we
> will of course be happy to discuss it with the agency.
>
> DR. BAXTER: Sure.
>
> DR. KATZ: Dr. Maxwell?
>
> DR. MAXWELL: A couple of things. There was a question about trying to
> find out where drugs come from on the street and, unless I am
> mistaken, the instrument that is given to the field interviewers, the
> last one I got, doesn\'t ask the question of where they got it. There
> is no question like that. Secondly\--
>
> DR. KATZ: Actually, maybe it would be better just to take one piece at
> a time.
>
> DR. MAXWELL: Okay, but that is not a question; it is just a
> clarification.
>
> DR. HADDOX: May I make a clarification as well? That is not the entire
> contact that the field researcher has. That is sort of getting
> started, the beginning of the structured interview. The goal was to
> allow that person to go in. Depending on what we are looking at, those
> questions are likely going to be asked. Okay? So, the document that
> you have in your briefing document is sort of the beginning.
>
> DR. MAXWELL: No, no, starting in June a year ago I was asked to be one
> of the field researchers\--
>
> DR. HADDOX: Oh, I am sorry, when we say field researcher we mean the
> people that we have hired to go out to investigate signals. You mean
> you were asked to be a key informant perhaps?
>
> DR. MAXWELL: Yes. Let me also clarify that the only zip code data that
> is collected from the key informants, from what I can tell, is the zip
> code where I live. In other words, if I sent in data from Ft. Worth it
> would not be reflected in the graphs by zip code.
>
> DR. HADDOX: We are aware of that and we are endeavoring to correct
> that right now by asking the key informants who are at treatment
> centers what zip codes does 85 percent of your clientele come from so
> we can try to extrapolate\--
>
> DR. MAXWELL: Okay, well, that was not in the June format. I wasn\'t
> going to get into that until the question came up. However, one thing
> I would like to ask is yesterday we saw the DENS treatment data which
> was unable for most states to break out OxyContin, and it showed that
> in the past users of OxyContin stayed out on the street for about ten
> years from your first use until admission to treatment, but in the
> last couple of years that has telescoped down to four years. Since you
> have the DENS data which does specifically ask about OxyContin in
> terms of our questions about the abuse liability and dependence, the
> question is are people becoming more addicted quicker with OxyContin
> as compared to other drugs? I would very much like to see the DENS
> data run looking at the lag on OxyContin as compared to other.
>
> DR, SCHNOLL: I don\'t have those specific data right now. We could ask
> Dr. McLellan to run that information for us but I don\'t have the
> precise information.
>
> DR. MAXWELL: Well, I realize that but it might be interesting.
>
> DR. SCHNOLL: Yes. Yes, that might be something we could do.
>
> DR. MAXWELL: Then, lastly, before we go forward with approving another
> drug I certainly would like to see more in-depth data. We have seen
> the presentation of what RADARS is going to do but I would really like
> to see data showing us all the data that has been collected, what is
> being collected, what is being done, how well the system is working so
> that we would feel more confident that when we then move into another
> drug the data are there and we know the system works.
>
> DR. SCHNOLL: We only had an hour this morning to present. We have
> extensive data on all of the drugs and just didn\'t have time, and
> what we selected were just examples to show you what we can do with
> the data system. I understand your request but there just wasn\'t the
> time to do that.
>
> DR. KATZ: I think one take-home message that I want to make sure is
> left is that it seems like it is important for the surveillance system
> to be able, at the end of the day, to distinguish what proportion of
> street abused drugs come from the prescribing relationship versus
> coming from diverted sources. So, it sounds like people are
> recommending that at the end of the day we will be comfortable that
> the system will be able to accomplish that.
>
> We are half an hour behind schedule and it looks like I have about 12
> people still with questions and I have my own questions. So, what I
> think I will need to do is take one more question and then we will
> have to go on to our next presentation, and Dr. Saini, you are next.
>
> DR. SAINI: We heard very good things about risk management but I did
> not hear anything from the pharmaceutical company regarding the NASPER
> program. Do you have any comments regarding that, please?
>
> DR. HADDOX: For those who are not familiar, Dr. Saini is referring to
> a Bill that is in Congress now that would make a federal prescription
> monitoring program that would be modeled on the CASPER program in
> Kentucky, which is an electronic program.
>
> Purdue is in favor of well-designed electronic, non-barrier
> prescription programs. In fact, we have supported those in a number of
> states. While we share the intent of the sponsors for the NASPER
> program, I have my own\--and I have discussed with other people both
> in and outside of government\--reservations about if it will be too
> unwieldy to be useful. There are a number of issues. It is very
> complex, as you are no doubt aware. But I think that prescription
> monitoring programs right now are being done on a state level. They
> have been shown to be effective and I think that we will have to see
> where NASPER goes but I have some questions and other people have
> raised other questions about is it just too big a data set to manage
> appropriately.
>
> DR. KATZ: I am going to take the privilege of asking one more question
> before we stop. We have heard from many people on the committee, and
> in terms of some of our lectures yesterday about the importance of
> monitoring the target population that we are prescribing these
> medications to for the development of negative consequences, other
> opioid use, including addiction. So, my question is what aspect of the
> risk management program that we are hearing about monitors our
> patients for those risks, and how is that data captured, analyzed,
> what are the outcome measures, etc?
>
> DR. HADDOX: Well, one of the key elements there is the adverse event
> reporting system where abuse and addiction are by definition serious
> adverse events. We monitor that on a regular basis. But that is a
> passive system, as was pointed out earlier. As part of our education,
> we believe and certainly our numbers would suggest that with the
> education we put forth with practitioners we are making that perhaps a
> little less spontaneous reporting system and that we are sort of
> heightening their sensitivities. So, certainly if you look at the
> numbers of cases that we have gotten in, we are getting more of that
> information and Dr. Schnoll has some comments.
>
> DR. SCHNOLL: Yes, we also have a number of key informants and
> physicians who specialize in pain management and so we will be
> collecting information from them regarding what they are seeing in
> terms of the development of addiction in their own patients.
>
> DR. KATZ: So, is it fair to say then that there is no prospective
> systematic means in this surveillance system for monitoring patients
> for the development of any of these complications?
>
> DR. HADDOX: I am sorry, I didn\'t capture that.
>
> DR. KATZ: I was just making sure I understood that. It sounds like the
> answer is that there is no part of the system that prospectively and
> systematically tried to get at the proportion of patients prescribed
> Palladone or any other opioid who develop any of these negative
> consequences.
>
> DR. HADDOX: Well, again in the interest of time, we do have a patient
> registry study with OxyContin that is an open-label extension study of
> a number of our trials. We are finding that the rates of aberrant drug
> taking behaviors or indicators of abuse or addiction are very low in
> that population, the intended population.
>
> DR. KATZ: Thank you. We need to move on to our next presentation.
>
> DR. APFEL: We forgot to respond to an earlier question about the
> pharmacokinetics of Palladone. We have checked back in the data and,
> as we suggested before, the accumulation of Palladone is very small.
> It appears to be less than 20 percent accumulation.
>
> DR. KATZ: Thank you. Well, let me again thank the sponsor for all the
> trouble they have gone to in putting together this information for us.
> We do appreciate all the effort that has gone not only into the
> program itself but also into the presentation this morning. So, again,
> I appreciate your time and efforts. Now we need to move on to our next
> presentation and I would like to introduce Dr. Silvia Calderon, whom I
> have been keeping on hold for half an hour now, who is an
> interdisciplinary scientist.
>
> Well, it has been suggested that I call a break and I can never say no
> to that type of suggestion so, good, let\'s a 15-minute break and we
> will begin then.
>
> \[Brief recess.\]
>
> DR. KATZ: Hello, again. Just to bring people up to date on what we are
> doing schedulingwise, we will have Dr. Calderone\'s presentation now.
> We will go straight through Dr. Kreek\'s presentation, then straight
> through to Dr. Hertz\'s presentation which will be briefer than we
> originally thought. Then we will be going straight through to the Open
> Public Hearing. There are a number of Open Public Hearing speakers,
> so, to make sure that we don\'t have any delays, I would request that
> anybody signed up for the open public speaking make their way up to
> this\--there is a row up in front towards my left reserved for Open
> Public Hearing speakers.
>
> So, in the near future, make your way up there so we don\'t need to
> hunt you down.
>
> Now, we will turn to Dr. Calderone from the FDA Controlled Substance
> staff who will speak with us about the FDA\'s perspective on the abuse
> liability of hydromorphone extended-release tablets.
>
> **Abuse Liability of Hydromorphone**
>
> **Extended-Release Tablets**
>
> DR. CALDERONE: Thank you very much.
>
> \[Slide.\]
>
> I will try to cover the abuse liability of hydromorphone
> extended-release capsules.
>
> \[Slide.\]
>
> Hydromorphone formulations have been marketed in the United States for
> many years as immediate-release tablets known as Dilaudid 2, 4, 8
> milligrams, injectables, different concentrations 1, 2, 4, 10
> milligrams per ml or a solution 5 milligrams per 5 ml and 3-milligram
> suppositories. Extended-release formulations are currently marketed in
> the United Kingdom and Canada to be administered once or twice a day.
>
> Palladone represents a new extended-release formulation under the FDA
> review which is under review by the FDA.
>
> \[Slide.\]
>
> The proposed strengths of Palladone are 12 milligrams, 16 milligrams,
> 24 and 32 milligrams per capsules. This new formulation is being
> proposed for the use only in opioid-tolerant patients and its proposed
> indication is for the management of chronic moderate-to-severe pain in
> patients requiring continuous around-the-clock opioid analgesia for an
> extended period of time.
>
> Palladone capsules will release the contained hydromorphone over a
> 24-hour period and, therefore, are to be administered once per day.
>
> \[Slide.\]
>
> As it was presented to you yesterday, hydromorphone is a Schedule II
> substance and shares the same schedule with other opioids such as
> oxycodone, morphine, fentanyl. The meaning of Schedule II; drugs in
> this schedule have a high abuse potential. They have the highest level
> of control for an approved drug and, in terms of regulatory
> requirement, prescriber and dispenser registration, separate record
> keeping by dispenser, distribution order forms, no refills,
> manufacturing security and quotas, import and export permits.
>
> Note that the CSA classifies substances by their abuse potential,
> dependence on by medical utility. We also know, note please, that the
> abuse potential, the actual abuse of a drug, goes beyond the abuse
> potential. There are several factors that contribute to the actual
> abuse of the drug.
>
> \[Slide.\]
>
> That is why, when we use the term \"abuse liability,\" we refer to the
> abuse potential of a drug, meaning pharmacological properties of the
> drug, and we incorporate, we take under consideration, a social and
> public-health factor.
>
> Under the social, we incorporate the human sometimes extremely
> difficult to predict factor. This equation also includes the use of
> synthesis, the availability of the drug, includes what is known about
> the drug, the information available of the drug. So it goes beyond the
> pharmacological properties. It also includes the pharmacokinetics, the
> chemistry, self-administration, drug-discrimination studies, but goes
> beyond that.
>
> So, therefore, abuse liability captures other factors and puts abuse
> potential into a social and public context.
>
> I want to also mention that usually sometimes these terms are used
> interchangeably.
>
> \[Slide.\]
>
> It is well known that mu opiate agonists produce diverse effects such
> as respiratory depression, analgesia, miosis, drowsiness and also they
> induce changes in mood including euphoria and liking. Hydromorphone,
> oxycodone, morphine, all are mu opioid agonists. They all share the
> same type of properties but they exhibit different relative analgesic
> and subjective effect potencies.
>
> When analgesia, miosis and respiratory depression are measured, oral
> hydromorphone is approximately four times more potent than oral
> oxycodone and morphine whereas intravenous hydromorphone is six to
> seven times more potent than morphine.
>
> It has been also shown that when euphoria and reinforcing effects of
> oral and intravenous hydromorphone were evaluated, hydromorphone was
> ten times as potent as morphine in drug-abusing subjects and in normal
> volunteers. Therefore, based upon these numbers, 10 milligrams or oral
> hydromorphone will produce comparable analgesia effects to 40
> milligram of oxycodone or morphine.
>
> On the other hand, the same 10 milligrams of hydromorphone will elicit
> an equivalent euphoria to 100 milligrams of morphine. It is also known
> another factor we consider in the evaluation of abuse liability is
> what is known about the history and abuse of the drug.
>
> \[Slide.\]
>
> Hydromorphone has a documented history of abuse in the United States
> dating back to the 1970s and it has been subject to the DEA Task Force
> attention. Hydromorphone was historically the drug of choice among
> opioid abusers who often administered the drug intravenously after
> crushing and dissolving the 4-milligram tablet. Also, DEA reported
> that the 4-milligram Dilaudid tablet street value averaged \$40 and
> that Dilaudid continued to be diverted and abused.
>
> In the next two slides, I will highlight some of the findings of the
> Drug Abuse Warning Network Medical Examiners component. Yesterday, you
> have heard about one of the other databases reporting in DAWN. That is
> the emergency department. But I will be talking about the medical
> examiner\'s component.
>
> Also, I will present to you rates, drug-abuse rates, per prescriptions
> dispensed and finally I will discuss the limitations that apply when
> calculating those rates. You will see there are many.
>
> \[Slide.\]
>
> The DAWN Medical Examiner\'s database reporting for the \'99-2001
> period 132 hydromorphone-related deaths and 1,272 oxycodone-related
> deaths for the same period of time. Adjusting these numbers by the
> total number of retail prescriptions, the death rates expressed as
> number of deaths per 100,000 prescriptions are 7.5 deaths per 100,000
> prescription for hydromorphone, 1.8 when considering the whole
> oxycodone market included single product and combination products.
>
> When recalculating that rate, if we only include in the denominator
> oxycodone single-entity products, that rate changes to 6.1.
>
> \[Slide.\]
>
> These rates should be, or these ratios should be, considered crude
> estimates. We know that the Medical Examiner deaths do not represent
> national estimates and we know that DAWN only captures 128
> jurisdictions out of 3,000 jurisdictions in the whole country.
>
> We also know that the DAWN Medical Examiner Report may include
> multiple drug mentions and the cost should not be attributed to any of
> the drugs my itself. We also know that DAWN really includes brand
> names.
>
> Talking about the limitations regarding the denominator, we know that
> sales data represents the whole U.S. market. We also know that the
> denominators include all formulations of the drug. Although far from
> perfect, the calculation of these crude rates is relied upon in the
> field of drug-abuse epidemiology and they have been used to put these
> numbers into a context.
>
> Having described all the limitations of the calculation, we might say
> that the difference in the rates might reflect hydromorphone\'s high
> potency. Maybe they reflect a different pattern of abuse or maybe the
> reports have been captured in different reporting areas.
>
> \[Slide.\]
>
> Based upon the data reviewed, hydromorphone appears to have higher
> abuse liability than other Schedule II opioids. When compared to
> immediate-release hydromorphone products currently available, due to
> high concentration of hydromorphone in the formulation, Palladone has
> higher potential risks of misuse and overdose than might result in
> death.
>
> Also, Palladone poses significant risk of overdose in
> non-opioid-tolerant patients or if Palladone is misused and abused.
>
> \[Slide.\]
>
> So, in conclusion, risk-management programs should be designed to
> address the risks associated with this high-dose opioid analgesia drug
> product and, as an example, Palladone.
>
> Thank you very much.
>
> DR. KATZ: Why don\'t you stay up there, Dr. Calderone. Are there any
> questions from the table?
>
> Dr. Skipper first and then Dr. Shafer.
>
> DR. SKIPPER: Thanks, Dr. Calderone. Do you, then, disagree with what
> Dr. Haddox said earlier that human and animal-abuse liability for
> hydromorphone was typically\--is morphinelike?
>
> DR. CALDERONE: I think we are confusing two terms. I totally agree
> that the subjective profiles of the drug are the same. They both are
> perceived different. We have higher euphoria, higher liking with
> hydromorphone and, in drug abusers, they would rather go for
> hydromorphone than for morphine in the same way that hydromorphone is
> perceived differently than codeine. They will actually see a
> differentiation.
>
> I think that this profile is the same but there are differences among
> the mu opioid full agonists.
>
> DR. SKIPPER: So the abuse liability is higher for hydromorphone?
>
> DR. CALDERONE: If we consider the human factor that is sometimes so
> difficult to predict because we cannot control, the abuse liability is
> higher.
>
> DR. SKIPPER: Thank you.
>
> DR. KATZ: Dr. Shafer.
>
> DR. SHAFER: A couple of things. I think that you have cherry-picked
> the data to make your presentation. If you take a look at various
> estimates of analgesic potency, relative analgesic potency, for
> hydromorphone and morphine, the Canadian package insert gives 7 to 11,
> based upon acute-pain studies.
>
> Hill and Zackney cite a figure of seven- to eight-fold difference in
> analgesia potency. Maher and Forest, 1975, give 8.6. Goodman and
> Gillman list 7.7. The only study that is approximately 4, which you
> cite, is the study by Dunbar of 1996.
>
> Similarly, if you look on the other side of the equation which is the
> subjective effects of the drugs, Jasinski actually gives a figure of
> 9. But if you look at the standard errors on that, it ranges from 0 to
> 20, so it is not an exact number. I mean, there is quite a broad
> variation there.
>
> On the scale of subjects liking, the particular thing about what do
> subjects taste when they get the drug, he actually gives it a 6.8
> which puts it right in the middle of the relative potency for
> analgesia. If you look at the scales that Jasinski has used and the
> maximum effect in terms of subjects liking, they are indistinguishable
> for morphine and for hydromorphone.
>
> Hill and Zackney give a figure of 10, which is the figure you cited.
> But, again, their standard errors on that range from 6 to 20. So it is
> not clear from looking at the data that were provided to us that it
> supports the conclusion that you have drawn.
>
> DR. CALDERONE: Hill and Zackney confirm, or they reported, ratio in
> terms\--when analgesia is measured, they compared 7 to 1. The equal
> analgesic dose they use is 7 or, I believe that they have gone to 7.7
> and their calculations were 7.7.
>
> In terms of Hill and Zackney, they also confirm Jasinski numbers. We
> have variability in terms of the scale. That is something that we face
> and it is part of the design and the methodology for these types of
> clinical-abuse liability. But I feel very confident we can report it
> as a ratio but I feel confident that the euphoria and subjective
> effects induced by hydromorphone, the rate is higher than equal doses.
>
> So an equal analgesia dose is the euphoria and the liking is higher.
>
> DR. SHAFER: All I will say is that the data that we were provided, the
> numbers don\'t line up.
>
> DR. CALDERONE: If you read the last conclusion from the Zackney
> paper\--for the Hill and Zackney paper\--he confirms a rate of 9 to
> 10.
>
> DR. SHAFER: I will read the conclusion if you want, but his actual
> words are, \"slightly higher,\" which is a little bit different than
> how it is being represented.
>
> DR. KATZ: Dr. Aronson.
>
> DR. ARONSON: I want to pick up on a point of your discussion. I think
> it is a segue from the question that was just asked prior. I
> appreciate your conclusions that this is a drug of choice by addicts.
> I understand the differences of those conclusions being drawn. But one
> of the comments that was made in this morning\'s series of discussions
> that continues to resonate in my mind was the estimation that there is
> about 5 percent of patients who have pain that will become addicts.
>
> What is your opinion? Is there data to suggest that the likelihood of
> that population, that specific population, not the addict population
> but the patient with pain who could become an addict\--is that chance
> greater with this drug in your opinion and is there data to support
> that?
>
> DR. CALDERONE: I don\'t we don\'t have data to support the actual\--to
> support iatrogenic addiction. What I think, it will be an actual
> estimate. I think that the percentage is very dependent on the paper
> you read. I know that those in Fishman reported, like, the incidence
> of the addiction in patients could go even from 5 and I believe it is
> up to 15 percent.
>
> So your question is the hydromorphone\--I would say that hydromorphone
> is a very potent and positive reinforcing drug. I think that we don\'t
> have a study to support that it will induce\--the rates of addiction
> will be higher with this drug.
>
> DR. KATZ: That is a research area of mine so I can contribute, I
> think. In terms of the question of what is the incidence of new cases
> of addiction in patients who were not previously addicted resulting
> from the therapeutic exposure to opioids for the treatment of chronic
> pain, the answer is that there are no studies that address that issue.
> It is not that there are conflicting studies. It is that there are no
> studies.
>
> The same is true for patients with risk factors for addiction. There
> are no studies that address that issue.
>
> Dr. Skipper?
>
> DR. SKIPPER: I just wanted to ask one follow up. Have we done anything
> to look at street value, I mean comparative, because it seems like I
> have read that hydromorphone has significantly higher street value
> than\--
>
> DR. CALDERONE: Actually, we don\'t do those type of studies. The
> information I presented was provided by the DEA but I really don\'t
> know if the sponsor and the RADARS data is collecting any type of
> information like that. I don\'t know.
>
> DR. KATZ: Would the sponsor care to respond to\--
>
> DR. CALDERONE: The sponsor might have some other information than what
> we have.
>
> DR. CICERO: I am Ted Cicero, again, from Washington University. Yeah;
> we do. I think, at least for OxyContin, the street value is about
> \$1.00 a milligram as it goes up. The hydromorphone, itself, is about
> \$40 a tablet, as best we can tell.
>
> There was also, I think, the question about potency. I think that was
> raised and I think one of the questions came up and if I can, I would
> just like to interject at that point. There is no data. There is
> absolutely no data to support the assumption that compounds with high
> affinity for the mu opiate receptor are intrinsically any different in
> their abuse liability.
>
> I think what is getting confused here is that potency is a very
> different issue in terms of efficacy than it is in terms of producing
> abuse liability. If you look at the data, all the data in humans and
> animals, if it has affinity for the mu receptor, it is guaranteed to
> have reinforcing effects and have a potential for abuse liability.
> Intrinsically that is a feature of all compounds that have an affinity
> for the mu agonist.
>
> The fact that one compound requires a microgram where another compound
> requires a milligram to produce the same effect is irrelevant. This is
> an important point because you are suggesting that a given compound,
> like hydromorphone, has more intrinsic abuse potential than another
> compound such as fentanyl. That is simply not correct and that is
> based on many other factors that enter into it.
>
> DR. KATZ: Thanks. Just to return to the program.
>
> DR. CALDERONE: I really want to go back to that question. I really
> disagree.
>
> DR. KATZ: Go ahead. Dr. Cicero, you can go ahead and sit back down.
> Thanks for your input.
>
> DR. CALDERONE: I really disagree with that statement. It believe that
> abuse liability is more than receptor occupancy, more than binding.
> There is a human component into the abuse liability. It is true, like,
> Goodman and Gillman even cites the abusers do not distinguish between
> heroin and hydromorphone and they do distinguish between heroin and
> any other opioids.
>
> If you have an abuser, will go for the hydromorphone, will not go for
> the codeine. So, although this is independent of the potency and the
> receptor occupancy, we know that abusers distinguish between opioids.
> That is why we try to incorporate the human component into the
> abuse-liability calculation.
>
> DR. SKIPPER: Would it not be\--I am just following up my question.
>
> DR. KATZ: If you could just, next time, indicate that and I would be
> happy to recognize you.
>
> DR. SKIPPER: Okay. I thought I was still recognized. But, anyway\--
>
> DR. KATZ: You weren\'t.
>
> DR. SKIPPER: Okay. My light was still on.
>
> DR. KATZ: You forgot to turn it off.
>
> DR. SKIPPER: Would it not be valuable to do some survey to see, at the
> street level, how addicts value this because wouldn\'t that be where
> the rubber meets the road, to take into effect the human component and
> is there any plan to do that?
>
> DR. CALDERONE: I don\'t know of any plan to do that, but I think that
> the study should be designed carefully. We need to think about\--the
> details of the study should be really clear. But it will be extremely
> valuable to have that information.
>
> DR. KATZ: Just to respond. There was a study published by Daniel
> Burkhoff a number of years ago who did go into a prison to patients
> incarcerated for opioid abuse and asked them to rate which ones they
> liked most to least. I forget the order, but hydromorphone was near
> the top of that list.
>
> Dr. Skipper and then Dr. Shafer and then Dr. Cush. Dr. Shafer?
>
> DR. SHAFER: Let me mention that the subject on the table here is a
> pharmacokinetically modified form of hydromorphone. That is very
> relevant because the one place where these drugs are distinguished is
> the rate of onset. Heroin has a very fast onset. There it is really
> the rate of crossing the blood-brain barrier.
>
> Hydromorphone has an exceedingly fast rate of crossing the blood-brain
> barrier and I am not surprised to know that subjects find the
> experiences very similar with I.V. dosing of the two.
>
> With an oral form which is intended to actually\--and, as you saw from
> the graph where the levels in the plasma rise very slowly, that
> pharmacokinetic difference between the two I.V. pushes of the drugs,
> or let me say the pharmacokinetic similarity in terms of the brain
> concentrations following I.V. push are virtually irrelevant, so it is
> not clear how extrapolatable those data are.
>
> DR. KATZ: I think, to summarize, it is clear that hydromorphone, by
> any form, has a high abuse liability.
>
> Dr. Cush?
>
> DR. CUSH: I don\'t have questions.
>
> DR. KATZ: Are there any other questions for Dr. Calderone based on her
> presentation?
>
> Thank you very much for speaking with us. Our next speaker will be Dr.
> Mary Jeanne Kreek, whom I am delighted to introduce. She is a
> professor and Head of the Laboratory of the Biology of the Addictive
> Diseases at Rockefeller University. Anyone who has got even the most
> tangential interest in this area will know that Dr. Kreek has been
> really a pilar of this whole field for an extended period of time and
> it is a privilege for us to have her here.
>
> **Long Acting Opioids: Challenges in Pharmacology**
>
> DR. KREEK: Thank you very much, Dr. Katz.
>
> \[Slide.\]
>
> Thank you all for inviting me to be here today. I have been asked to
> speak today on the general topic of challenges with long-acting
> opioids. What I am going to cover today will really be a mixture of
> topics but really focusing on my perspective which is addiction and
> the treatment of addiction.
>
> I really have to put up for something that is not on any slide, but I
> will be addressing different kinds of problems related to long-acting
> versus short-acting opiate use, some of the nuances, some of what I
> perceive, at least, are the societal needs at this time.
>
> But, at the same time, I would like to point out one question that I
> think has not been asked today and I am going to put it up front
> because I think it is very central to when you are considering abuse
> liability, and that is who is the abuser and who is participating in
> abuse. It is an additional question to the very cogent superior
> questions I heard about where is it coming from, how is it coming, how
> is it getting to the abuser. Those are all very, very important
> questions. But who is the abuser is also a critical question.
>
> I will tell you from years of trying to answer that question, being
> forced to answer that question, I have found that most of the abusers
> in our urban centers are persons who actually have heroin addiction
> and are looking for either sustaining their heroin addiction and/or
> unable to get into treatment.
>
> I think one thing I would like to say a priori; we must, as a society,
> I think, accept addictions as diseases separate from each other in
> their later forms and we must aggressively treat those addictions so
> we decrease the numbers of persons at risk while\--and I am primarily
> a scientist\--we try to learn more about the basis of addictions, who
> is vulnerable, what are they vulnerable for and how can we do better
> primary prevention as well as early intervention.
>
> Those are kind of philosophical comments, but I think they need to be
> said and we do need to ask who are the people misusing drugs of abuse.
>
> \[Slide.\]
>
> In terms of major issues, I am going to start with my summary first
> and then I will go into some of the specifics. Your handout, handed
> out today, if you got a colored copy, is actually easier to read. If
> you didn\'t, I\'m sorry, but it will go into things I certainly won\'t
> have time to cover.
>
> Major issues; I think education is critical. How we are going to do
> education, how the FDA, DEA, all our wonderful regulatory
> organizations and our scientists and our schools and our private
> sector can all provide education. We all have to work together to do
> it.
>
> There are some major problems very specifically related to physician
> use or prescribing of long-acting opioids. They are major problems
> that I think we need to think about addressing generically as well as
> specifically.
>
> One, there has been a lack of education in recent years of classical
> pharmacology, pharmacokinetics and pharmacodynamics. That is a general
> statement that I think we all will concur. Look at medical students
> now as opposed to five, twenty and thirty years ago.
>
> However, having said that, that is no excuse. It needs to be updated
> and it needs to be made adequate. One of the real gaps I have found,
> as I have lectured to scientists but also physician-scientists and
> physician groups, is the lack of knowledge about long-acting versus
> short-acting opiates, mu opioid receptor agonists.
>
> That is astonishing. I also find that lack of knowledge with DEA and
> FDA and others in regulation as well as many other lay people. So I
> think we need to worry about the medical education. We also have had
> both discovery, synthesis and development of both intrinsically
> long-acting, methadone, LAAM, buprenorphin as well as formulation of
> short-acting compounds into long-acting preparations.
>
> \[Slide.\]
>
> There is also a lack of medical-school and other healthcare
> professional and neuroscience education about addiction. The specific
> addictions, approach to treatment, identification, diagnosis and
> management. There is a real lack of awareness of prevalence. 10 to 20
> percent of all Americans have an addiction. Look around the room.
> There are a lot of you.
>
> There is lack of knowledge about genetic vulnerabilities, predictable
> chronic-drug-use induced changes in the brain and environmental
> factors ranging from early prenatal and perinatal problems to set and
> setting, peer pressure, availability and host factors.
>
> So we have physicians as well as other healthcare professionals who
> don\'t know enough about the long-acting versus short-acting mu
> agonists pertinent to today\'s discussions and we also have physicians
> and healthcare professionals that have been taught very little about
> addictions.
>
> There are medical schools that do a very good job in one or both and
> there are some that do a poor job in both. The same is true for
> nursing schools, for science educators at the post-graduate level. We,
> therefore, have problems. Inadequate knowledge; that can lead to
> increased morbidity and mortality which I am also concerned about.
> Today is focused on abuse liability, but I can concerned about the
> deaths that occur when physicians misprescribe because of lack of
> knowledge.
>
> \[Slide.\]
>
> There are also physicians with inadequate time. The pressures of HMOs
> force many physicians to be close to script writers even though they
> didn\'t plan to do and they don\'t want to be. The majority of
> problems lay in these two realms; inadequate time, inadequate
> knowledge. Some do wish for profit or are willing to, for diverse
> reasons, become prescription writers; that is, the illicit practice of
> medicine.
>
> I do think this is also important. Similar constraints of specific
> education and time lead to inappropriate enforcement. I have had the
> great privilege to teach many DEA field officers about long-acting
> versus short-acting opioids and when it is appropriate to use which. I
> have to say, they have been incredible responsive. Denise Curry and I
> have discussed over the years how wonderful it would be to have even
> broader teaching manuals for our enforcement people. This, of course,
> is in our context of pharmacotherapy for opiate addiction.
>
> \[Slide.\]
>
> What are the prevalences of addictions in the U.S.? Approximately 15
> million alcoholics, 2 million cocaine addicts and about 1 million
> heroin addicts. You see absolutely lacking on this slide persons who
> are addicted to licit drugs and broken out by type like mu agonists.
> We actually don\'t have those data. We have talked about it today, the
> need to general better data, more data.
>
> Many groups have tried. It has been very difficult to do so. It needs
> to be done much more thoroughly. There will be inherent problems even
> if one does a better screening. For instance, we have just heard by
> the DAWN network, you get a denominator that is simply compound. It
> cannot be finer than compound. You do not know the formulation, the
> route of administration, the mode of administration, when you do such
> kind of detection.
>
> This is something that I may or may not get to today but I want to
> point out that approximately 1 in 10 to 1 in 20 who self-expose to
> alcohol become alcoholics. About 1 in 10 to 1 in 20 that self-expose
> to cocaine become cocaine addicted. About 1 in 3 to 1 in 5 that
> self-expose, nonprescription, non-medically indicated, to heroin,
> become heroin addicted.
>
> Again, this becomes terribly important when one considers the question
> of who is misusing or abusing a drug such as an opiate formulation. Is
> it someone is already addicted? Is it somebody who is a drug abuser
> trying a lot of things? I think we could expect to see very different
> kinds of outcomes depending on how we define the terms. Critical.
>
> \[Slide.\]
>
> What are the factors to develop an addiction. This is actually a very
> early formulation from my lab but I don\'t think there is much
> controversy about the three major types of components. We now know
> that, of course, environment plays a very important role and I have
> run over some of these, set and setting, cuing, comorbidity, both
> psychiatric and medical, as well as peer pressure, stress and
> stressors which is on some of your handouts, not on others, I am not
> going to get into today.
>
> I would be glad to come talk another time about that, but we know that
> stress and, indeed, pain is a stress, stress alters responsivity. But
> there is evidence to suggest in the setting of pain, there is less of
> a pleasant euphoric drug effect and more of a pleasant relief-of-pain
> effect.
>
> Genetic factors. This is sobering but many studies have shown that 25
> to 50 percent of the relative risk of developing addiction is on a
> genetic basis. The studies for alcoholism are three decades old. The
> studies for other drugs of abuse are much more recent. However, there
> is a controversy about whether or not there are specific genes
> dictating for specific addictions.
>
> Our own formulation is closer to that of Ming Swann at Harvard which
> is there will be many polymorphisms of many genes contributing to any
> addiction. If one happens to have depression or anxiety syndrome, the
> genes contributing to those disorders may also contribute.
>
> But there will also be some variants that are very specific for
> specific types of drugs of abuse. I think the data, not only
> epidemiology but of specific polymorphisms, is beginning now to bubble
> up to support that Swann hypothesis which we also agree with.
>
> Drug-induced effects. This is extremely important. The people to my
> left may get nervous about it but we know that chronic exposure to
> drugs of abuse alter the brain. We also know, however, that the on/off
> effects of drugs of abuse alter the brain in ways that sometimes
> steady state doesn\'t. Now the people to my left will feel very happy
> because what my lab has shown is that the more one approaches steady
> state, the less problems you get in altering the brain and those very
> brain changes may contribute to the behaviors that we know as
> self-administration and addiction. It is a powerful statement.
>
> \[Slide.\]
>
> We know the endogenous opioids are involved in each of the addictions.
> I have heard no discussion of those today. Probably it is in more
> arcane sessions but, in fact, we are always talking about the
> competition between the need for more, the lack of enough endogenous
> opioids and, therefore, the administration of exogenous opiates,
> whether it is for the relief of pain or modulation of other systems.
>
> \[Slide.\]
>
> The mu opioid receptor was cloned about a year after the delta
> receptor was cloned by Kiefer and Evans, and Leah Yu and George Uhl.
> Two groups simultaneous came up with a mu receptor which is this
> longest one and which has more unique amino acids, primarily because
> of its length, with the other uniqueness of each of the three
> receptors residing in this extracellular and intracellular space where
> binding occurs and where signal transduction occurs.
>
> This is going to be important. I am sure this committee has seen come
> and go kappa ligands and will see coming and going delta ligands as
> well as mu ligands. They have some actions in common, some
> differential actions and they, in part, mimic the endogenous opioid
> system.
>
> \[Slide.\]
>
> It was alluded to by Dr. Katz that I have been in the field for some
> years and sometimes my former mentor, Dr. Dole, likes to refer to the
> fact that I started when I was five or six, which is very
> complimentary. But in 1964, I had the opportunity, as a first-year
> resident in internal medicine to cross 68th Street from what is now
> Cornell Medical School New York Hospital to the Rockefeller University
> to join a team that was then coalescing headed by Dole who recruited
> two women, Dr. Neiswander, a seasoned psychiatrist working in
> addiction, and myself.
>
> As we would, like with this people that Marie sent us to see on the
> streets of New York and the prisons and the detox centers, Vince and I
> became convinced, and now I think there is incredible data to support
> it, that heroin addiction is a disease. It is a metabolic disease of
> the brain with resultant behaviors of drug hunger, drug
> self-administration, despite knowledge of negative consequence to self
> and others.
>
> It is not simply a criminal behavior or due alone to any sort of
> personality or other personality disorder. The elegant studies of
> Weisman and Ronceville and others have shown that a wide spectrum of
> psychiatric disorders may be comorbid conditions. Indeed, if you look
> at the flip, about 40 to 50 percent of heroin addicts have no comorbid
> condition.
>
> \[Slide.\]
>
> Heroin is very short-acting in self-administration, therefore,
> self-administration occurs three to six times by the heroin addict.
> When they can\'t get heroin, they will look for another reinforcing
> drug. And, yes; intravenous hydromorphone, intravenous morphine, are
> high on that list.
>
> When they can\'t get a reinforcing agent, they like to get illicit
> methadone. It has been out there. It was called \"dollies\" when we
> began our work, dolapinhydrochoride, and, in fact, they would all say,
> \"If you can get nothing else, take a dolly. It will help you get
> through your withdrawal symptoms.\"
>
> Now we hear illicit use of methadone by many who are saying, \"Take
> methadone and self-medicate while you are waiting to get into a
> treatment program.\" We have inadequate treatment programs primarily,
> I believe, because medical education has not taught this is the
> disease that must be addressed by physicians and all the manpower that
> goes with physicians, healthcare personnel, in general. I think that
> is extraordinarily unfortunate.
>
> If you look at this arrow which follows our narcotics blockade
> tolerance paper of \'66, you will see the what we ask after the first
> studies where we had found that one could induce people into treatment
> with this compound, and I will come back to that in a minute, we had
> to study its safety.
>
> \[Slide.\]
>
> What were our goals in \'64 for a medication to treat an addiction? I
> present these because I think they are critical for treating an
> addiction but what we have learned, and what we had learned by the
> first ten years of our work, made us begin to education pain
> specialists. I think some of you may cringe on the committee but, in
> fact, it was crossing the street to Memorial that allowed us to help
> share what we were learning with Dr. Hood, Dr. Foley, Dr. Portenoy,
> names known to many of you, about the potential efficacy of
> long-acting opioids and, contrary to my medical-school education, that
> tolerance develops much more slowly when you have sustained opioid
> level than when you have intermittent opioid level, something now
> readdressed and affirmed in animal models by many groups.
>
> So we wanted a long-acting opiate to prevent withdrawal symptoms, to
> reduce craving and also to normalize any physiologic function
> disrupted by drug use. We wanted to target treatment agent to a
> specific site of action such as the receptor.
>
> Dole, along with Collier and Martin, and our group, the three of us at
> Rockefeller, we talking about opiate receptors in \'63, \'64, as the
> work was conceptualized and then initiated in \'64. But the receptors
> were not fully defined satisfactorily until \'73 when Schneider,
> Teranius and Simon, all three, did so within a month.
>
> \[Slide.\]
>
> We also wanted a medication that was orally effective. Why? To get
> away from the lore and the dangers, then hepatitis B, later HIV, now
> C, of use of needles, sharing of needles. We wanted a\--and I think
> this is critical and not necessarily satisfied in some formulations
> into long-acting, perhaps of long-acting, drugs a slow onset of
> action, a long duration of action and a slow offset of action.
>
> Now, there are two kinds of long-acting compounds, but, at that time,
> we were looking for one with intrinsic long-acting properties.
>
> \[Slide.\]
>
> Ray Hood had been, as part of the U.S. government, in postwar Germany
> and had brought this compound back thinking it might be good for pain
> management. It had never been brought to the clinic in any of its
> studies in Europe. This compound was studied by Hood at Memorial and
> Beecher at Harvard. I am sure some of you have read the classic papers
> where they found a single dose of methadone was similar to morphine
> and efficacy of about three to six hours.
>
> But when multiple doses of morphine were given to an opiate-naive
> person, both Hood and Beecher saw respiratory depression ensue. They
> knew, therefore, that methadone would not be good to give to
> opiate-naive or weakly-naive persons. They, therefore, dropped it from
> much more studies for pain and, in fact, it had been used only very
> modestly by the Lexington group for short-term detoxification of
> opiate addiction.
>
> But when I read that study, or the studies, from Beecher and from
> Hood, it became apparent to me that, even though we had no gas
> chromatography, no radioimmunoassay, we had to look and talk to
> patients to make our observations, that this compound might be
> intrinsically long-acting and, clearly, morphine and heroin, in its
> diacetyl man-made variant, are not. They are very short-acting.
>
> \[Slide.\]
>
> So we started with low-dose methadone 10 to 20. This is an induction
> which is still recommended for methadone and buprenorphine. Start with
> low doses and taper them up even when you have evaluated that a
> patient is tolerant, then, going up still slowly, so that the degree
> of tolerance was never exceeded. We found that a person could be
> totally functional behavioral with no drug craving.
>
> \[Slide.\]
>
> In our cross-tolerance studies, we superimposed intravenous heroin,
> intravenous hydromorphone, intravenous methadone and intravenous
> saline against the background in two series, each four weeks long, of
> Latin square, double-blinded designs. We found that 80 to 100
> milligrams a day of methadone would blockage against the intravenous
> effects of up to 200 milligrams of heroin.
>
> Now, these were important studies that have been replicated four times
> for methadone, two times for buprenorphine and two times for LAAM.
> Cross tolerance develops. Cross tolerance is critical.
>
> When we introduced the concept that methadone, indeed, is superb for
> management in chronic-pain patients, and parenthetically has become
> the major analgesia of choice in several countries, we taught
> induction, stabilization, but here to stay just over the degree of
> tolerance developed by an individual to be able to achieve pain
> relief.
>
> And the groups doing that find that much lower doses sometimes in the
> realm of 30 to 50 mgs a day are adequate.
>
> \[Slide.\]
>
> One can see this tiny bump clinically observed. We found that, indeed,
> methadone was profoundly different; oral onset after 30 minutes,
> duration of action 24 to 36 hours and withdrawal symptoms after 24
> hours. But it was not until a few years later, about nine years later,
> that Chuck Interisi and I independently developed gas chromatographic
> methods for measuring plasma levels of methadone.
>
> What one sees after an oral dose is this modest rise, barely a
> doubling of the nadir and then a steady state over the 24 hours. The
> 22 to 24-hour data were not published until 2000 when Jay Pett let us
> publish it as part of a PET study. It is flat as a pancake.
>
> When methadone is used in divided low doses for management of pain,
> most of my colleagues in pain management prefer to give it two times a
> day or sometimes three to get this modest little bump. It is not
> necessary to do so and we hold their hands, but patients sometimes
> feel more comfortable having that bump.
>
> Heroin has a half-life of three minutes, its 6-acetyl metabolite, 30
> minutes and about four hours for the active monitor metabolite.
> Methadone, both Interesi and I learned, in its racemic for use in
> therapeutics for pain or addiction has a half-life intrinsically of 24
> hours. Using stable isotope techniques with selected ion monitoring
> GAMS, we learned that the active enantiomer has a half-life of
> 48 hours. This is what we find at the 22 to 24th hour after methadone
> dose, flat as a pancake.
>
> \[Slide.\]
>
> We went on to ask how much occupancy of the brain is required working
> with Eckelman here at the NIH and Kenner Rice, we first were able to
> map thirteen major regions of the brain for mu receptors not done
> before this study. We have a steady-state ligand for radionuclide as
> long acting as is the compound and we found that, indeed, the pain
> regulation center of the thalamus has the highest amount of mu
> receptors in healthy humans followed by the limbic system which we
> know is involved in reward, emotion and addiction, the amygdala, the
> anterior cingulate as well as the nigra-striatal system also involve
> in long-term memory and consolidation, the caudate and putamen, part
> of the nigra striatal system.
>
> \[Slide.\]
>
> Shown in the orange bars, as we predicted, there is less than 20 to 30
> percent occupancy by methadone during steady state when doses of 80 to
> 100 milligrams a day, adequate treatment doses for many patients, are
> used.
>
> \[Slide.\]
>
> We know that this was a predicted result since our laboratory and
> others had shown that each of these functions, disrupted by the on/off
> effects of short-acting opiates such as heroin including stress
> responsivity, gonadal function, immune function as well as other
> functions such as GI function, not mentioned here, all normalized
> during steady-dose methadone treatment.
>
> So, 20 to 30 percent occupancy allows 70 percent or more of mu
> receptors coupled and ready to go with the endorphins acting there for
> their normal modulation.
>
> \[Slide.\]
>
> There are now 200,000 people in the U.S. in treatment with methadone.
> That is about one-fifth of the estimated persons eligible for
> treatment and methadone is still hampered by regulations that insists
> there be one year of heroin addiction, multiple regular
> self-administration. The one alteration when buprenorphine was
> approved last year by the FDA for treatment of addiction was DSM-IV
> diagnosis of addiction was allowed as entry. That would be about two
> to three months of daily multiple self-administration in most cases.
>
> We know that there is a voluntary retention in good programs which use
> 80 to 150 milligrams a day of methadone combined with adequate doses
> of behavior and counseling as documented by the McLellan-O\'Brien
> group to be essential and that heroin use steps down so that, by one
> year, less than 20 percent of programs using adequate medication and
> behavior had any illicit heroin.
>
> \[Slide.\]
>
> When you see higher uses than that, you have to be concerned. We also
> have learned several things about this compound. All mu opiates are
> not alike. They are full agonists. They are partial agonists. A
> beautiful example of a new treatment medication that is a partial
> agonist is buprenorphine.
>
> Mu agonism is a characteristic of methadone with probably the fullest
> agonism of any compound according to Steve Childers latest
> cell-biological work. Also, after the cloning, one could ask the
> question of what happens when endorphins bind to opiate receptors. You
> probably all know that they internalize and we now know that only two
> of the exogenous compounds robustly internalize after binding and the
> only one used in pharmacotherapy is methadone. It behaves exactly like
> beta-endorphin and metencephalon.
>
> It binds to the receptor and goes inside. So what? We don\'t know yet,
> but we think it may, in fact, have a great deal to do with the rate of
> development of tolerance\--tolerance. Remember tolerance and physical
> dependence are dissociable different molecular phenomenology.
>
> I was pleased to hear Dr. Kleber deny DSM-IV and say dependence is not
> addiction. I hope we can get the term changed. 100 percent of
> long-term opiate-treated persons for pain are opiate tolerant and they
> are opiate dependent. They are not addicted. Addiction means
> compulsive drug seeking and compulsive drug taking despite negative
> consequences to yourself.
>
> A methadone-treated patient who was no longer using illicit heroin is
> no longer a heroin addict. If they are not illicitly abusing cocaine
> or another drug, they are no longer an addict. They are a former
> addict in management with opioid pharmacotherapy. Our semantics are
> critical if we are going to communicate.
>
> Now, I heard today two or three different people say not more than 5
> percent of pain patients become addicted. Those are the guesstimates
> that are usually out there. There have been no rigorous prospective
> studies. They are very tough to do. We appreciate that.
>
> 5 percent is not nobody and 5 percent is a number that I think may, in
> fact, be correct because we do know there are certain persons that
> come off their need for opiates. Their pain source is gone and they
> cannot be tapered off. I will say I think the very best pain doctors
> continue to manage them and manage them correctly.
>
> Some pain doctors are nervous about that. The patients, therefore, do
> doctor shop. When they doctor shop, they get the label of addict. We
> all, in our treatment resources, have some persons referred to us who
> have been shoppers. Others simply difficult-to-manage pain patients
> and other persons that no longer need it.
>
> The final \"twofer,\" if you will, with methadone, or maybe it should
> be a \"threefer,\" now, full agonism, internalizes like endorphins and
> both enantiomers have NMDA-antagonism modest activity. Therefore, like
> the MK801 which started in the clinic and failed, but we know that
> NMDA antagonists do attenuate tolerance.
>
> So it is hard to dissociate with methadone whether the very, very slow
> development of tolerance is because of full agonism, internalization
> or NMDA antagonism or some combination of above.
>
> \[Slide.\]
>
> Now, we know that desirability, craving, hunger lead to
> self-administration. We know the dopaminergic system is involved in
> this and we know that certain regions of the brain play a real role,
> and we know that mu agonists can alter dopaminergic function. But
> there is ample evidence, including the work from Koobenbloom and from
> our own lab suggesting you can get rid of dopamine and there is still
> self-administration.
>
> You get rid of the mu receptor and there is no self-administration.
> However, I think key to all the considerations of any compound is in
> the reinforcing properties of opiates and, to date, most but not all
> other drugs of abuse, the exception being the hallucinogens. But the
> rapid rate of rise, be it of heroin or of cocaine, in blood and
> presumably brain are positively related to their reinforcing effects.
>
> So if you recall that first curve of heroin, rapidly up, rapidly down,
> the rapid fall from blood and brain of drugs of abuse are positively
> related to the onset of the negative reinforcing or withdrawal
> effects. So, ideally, one wants to achieve a steady state.
>
> \[Slide.\]
>
> Now, unfortunately, many formulations try to achieve that, but the
> flatter the curve, the better, the slower the onset the better, and
> the less possibility there is for crunching, mooshing or whatever
> terms are currently used in the package insert, the better.
>
> I would argue that intrinsic properties are even better because
> intrinsic properties you don\'t have to worry about formulation. You
> take the compound as it comes. We have been able to show\--and those
> of you who are rat and mouse doctors, like I am part of time,
> methadone is the fastest half-life of the mu agonists in the rat and
> mouse. 48 hours in humans for the active enantiomer, 24 hours for the
> racemic.
>
> Half-life in a mouse is 60 minutes. Half-life in rat is 90 minutes. So
> if you read a study on methadone in the animal, you have to rethink
> that.
>
> \[Slide.\]
>
> LAAM is also very long-acting. LAAM is enjoying some use but not a lot
> because of the QT interval. I would love to speak to the FDA about the
> QT interval issue another time. We have very good computer-driven EKG
> machines now which is overreading in every medication. So we have got
> to get the cardiologist to weigh in what is clinically relevant. That
> is across the board for AIDS drugs, phychotrophic drugs, opiate drugs,
> et cetera.
>
> LAAM has metabolites that are active, unlike methadone, and the
> metabolites make it even longer acting.
>
> \[Slide.\]
>
> Buprenorphine approved a year ago is a compound which is a partial
> agonist, no oral prep. The sublingual prep, however, has enormous
> abuse liability in many countries of Europe and India.
>
> This has led to its being recommended to be formulated with naloxone.
> The first naloxone preparation with an opiate was done in 1972 when we
> published a paper in 1973 that I bet not more than three in the room
> have read where we combined naloxone with methadone. The problem was
> we didn\'t need it because methadone is an extremely boring drug.
>
> I showed you its profile when given orally. It has a very slow onset
> of action and, even if you give it intravenously, it binds to every
> plasma protein which we later were able to elucidate. Its first pass
> through the liver is not rapid biotransformation. We showed in a
> perfused live prep, it is bound there and is slowly released like a
> gigantic spantab. So it sticks to all proteins, specifically and
> non-specifically. It is released from the liver. Unchanged methadone
> comes out in bile, undergoes enterohepatic and comes into the blood
> stream as unchanged methadone.
>
> For most compounds, that is not true. Buprenorphine intravenously does
> have a very rapid onset of action. Therefore, many abusers would take
> the sublingual prep elixir and inject it to get a high. By adding
> naloxone, naloxone has a half-life of only thirty minutes so you
> don\'t protect all the opioid-agonism effect, but you blunt the high.
>
> The same was true with the old T\'s and blues problem where naloxone
> was added to pentazazine which was being used intravenously. You
> prevent the high by adding the naloxone, therefore decrease the
> bioavailability. Whereas buprenorphine has a long dynamic action of 24
> to 48 hours, its half-life is extremely fast, three to five hours. Its
> sustained action is due to its very long mu-opioid-receptor occupancy.
>
> That occupancy is so tight, however, that, in the anesthesia
> literature, some of you will be aware of a few anesthesia-overdose
> deaths where naloxone and naltrexone and namefine could not reverse
> the effects of buprenorphine, not many when taken by the sublingual
> route. The maximum effective dose in humans is 24 to 32 milligrams.
> Unlike the rat, there is not an inverse-agonist effect.
>
> \[Slide.\]
>
> The treatments for addiction now. The effective ones are the top
> three, methadone maintenance, LAAM maintenance and
> buprenorphine-naloxone maintenance which are comparable except for the
> fact for those with high degree of tolerance and physical dependence,
> the highest dose, effective dose, of buprenorphine, 24 to 32 mgs,
> approved 16 mgs, is the equivalent only to 60 to 70 mgs of methadone.
>
> The Hopkins group of Stitzer and Bigelow have recently reproven our
> early data that the majority of patients need 80 to 150 a day of
> methadone and, in fact, with the purity of heroin now so high in the
> Northeast, it may be even higher.
>
> So, to conclude, to provide the most effective treatment for major
> addictive disease we need to have a combination of behavior and
> pharmacotherapy and mu agonists are our answer for those long-term
> heroin addicts and other opiate addicts. To provide the most effective
> treatment of pain, we need long-acting mu opioid agonists.
>
> \[Slide.\]
>
> We need them both. So I would propose that any healthcare provider
> should ask the following questions of themselves when thinking about
> using a medication. Is the medication formulation short-acting or
> long-acting. That is not a judgmental question. That is an academic
> question. I put up front, I think, for chronic pain, long-acting is
> better.
>
> On the other hand, you have to know what long-acting means, what its
> ramifications are, what its dosing intervals are, once a day, twice a
> day. You have to know precisely what its onset and offset are.
>
> You secondly have to ask is this patient opioid naive, modestly
> exposed, long-term exposed, and thus tolerant. Long-term formulations
> are really not appropriate for anyone who is not long-term exposed and
> tolerant.
>
> Finally, you have to ask the question, does this patient have a
> problem with some kind of drug abuse or addiction. Most of our
> patients come to us with family histories of alcoholism, not other
> drug abuse, because the other drugs were not so available two
> generations ago, one generation ago.
>
> Or are there other indicators suggesting increased vulnerability. Do
> you need to treat persons with vulnerability to develop a addiction
> for pain? You bet you do. You need to treat persons with an addiction
> who have bona fide pain as well.
>
> People ask me about managing methadone maintenance. I will tell you
> what you have to do is use a short-acting opiate superimposed on the
> steady state of long-acting. Don\'t increase the long-acting. It
> won\'t work for acute pain. Superimpose it and then back off quickly.
>
> But we need to ask these questions\--I would argue we need to make
> every physician do a check list to ask these questions and say, \"Have
> you answered each one of these?\" before you make your prescription.
>
> \[Slide.\]
>
> This is simply the compounds we could be talking about.
>
> DR. KATZ: Dr. Kreek, I am going to have to ask you to wrap up because
> of the schedule.
>
> DR. KREEK: That\'s it.
>
> DR. KATZ: Thanks very much for your insights. I appreciate it. I think
> we should take the time for a question or two. Dr. Bril, you were
> first.
>
> MR. BRIL: Thank you for the fascinating talk. I guess my fundamental
> question then would be what is it about this class of receptors that
> results in an irreversible change, I guess, because your addicts
> really need to be on a sustained methadone program or some exogenous
> opiate instead of endogenous production looking after the receptors.
> What happens that causes that?
>
> DR. KREEK: Actually, you have hit on something that is the origin of a
> lot of research, is there some way that we can make the endogenous
> opioids do the job. And the answer is acupuncture doesn\'t get it up
> there high enough and all the blockers of biotransformation of
> encephalins have not worked to date.
>
> It is a laudable goal. I will ask, are there other examples where
> brain changes occur and, indeed, with many diseases, there are
> examples of the brain changes occurring. Some of the changes occur in
> Parkinsonism and Alzheimer\'s and other neurodegenerative diseases
> have some parallels in certain aspects of each of the addictions.
>
> We know that, in endocrinopathies, in general, and I would say as a
> class of diseases, the addictions come very close to some of the
> endocrinopathies where one has an excess, either sustained excess or
> pulsatile excess, of hormones. One can see changes downstream from
> receptors in signal transduction systems and, on further downstream,
> in integrated, if you will, in this case, neurobiology.
>
> So the fact that short-acting drugs of abuse, and I could have shown
> you three zillion, mRNA, peptides, proteomics, what have you, that
> change, very notably, for the opiates, constant interactive receptor
> bombardment with a short-acting opiate like heroin, like morphine,
> alters the gene expression of genes that regulate our stress
> responsivity, for instance CRF and CRF receptor. Those are downstream
> events.
>
> But these, then, in turn alter behaviors. What we find when we give a
> steady dose which is actually moderate or high, depending on your
> perception, you undoubtedly increase the thermostat to a certain point
> that a new homeostasis develops.
>
> You can call it homeostasis, as you will recall from med school, until
> it becomes disproportionate. Then it becomes disruptive and the word
> allostatis is used by McCuen and Koob and others for that state. But
> we know that a steady dose of, for instance, methadone, LAAM or
> buprenorphine actually allows objectively studied disrupted physiology
> to normalize.
>
> We have many published studies as do many other people. So I can show
> those to you. But notably is stress responsivity which our own group
> thinks is quite central to the acquisition and development of
> addiction. What I didn\'t get to show you but we now have some
> polymorphisms that, in fact, alter binding to beta-endorphin.
>
> \[Slide.\]
>
> Look at the two right-hand panels, signal transduction after
> beta-endorphin binds. Beta-endorphin requires, obviously, the full
> integrity. This polymorphism, one in five of you in this room have a
> copy of, the allelic frequency is that high. Friends of ours at
> Hopkins proved what we predicted. They got there first. My people were
> furious.
>
> \[Slide.\]
>
> You give naloxone challenge, a paradigm we developed. If you have one
> copy of this very common polymorphism, you have different stress
> responsivity than you do if you have the heterozygote shown in blue.
>
> \[Slide.\]
>
> My friend Chuck O\'Brien did another study I asked him to do, please.
> He had studied naltrexone for treatment of alcoholism which you guys
> approved a couple of years ago down here\--many years ago, actually.
>
> He and Krantzler got together. They went back and consulted their
> patients who had been in a naltrexone trial because they were
> consented for genetics at the time. This paper is just now coming out
> in Neuropsychopharmacology. What Chuck and Hank were able to show is
> that persons with one copy of this variant are the ones that respond
> to naltrexone treatment for alcoholism, nobody else.
>
> So there is a lot of exciting stuff coming along with polymorphism. No
> doubt, the genetics are playing a role. I can\'t tell you a thing
> about addiction yet. That is not true, but I can\'t tell you because
> the paper hasn\'t come out yet. I can tell you that the polymorphisms
> are going to begin to be essential, gentlemen\--I\'m sorry\--for
> studies of pain management in the future, in the very near future.
>
> Thank you.
>
> DR. KATZ: Thanks very much for your insights, Dr. Kreek. We appreciate
> it.
>
> We are going to move on now to the FDA presentation. We are going to
> hear from Dr. Sharon Hertz who is the Team Leader in the Division of
> Anesthetic, Critical Care and Addiction Drug Products.
>
> **FDA Presentation**
>
> DR. HERTZ: I can start off with a little good news, I have no
> intention of speaking for an hour so it will be just a few minutes.
>
> \[Slide\]
>
> I am going to talk a little bit about some of the challenges. We have
> heard a lot about challenges throughout the last day and a half. I am
> going to talk about some of the challenges for the risk management of
> modified-release opioids, specifically some of the issues and
> challenges that we have seen when looking at the proposed plan for
> Palladone.
>
> \[Slide\]
>
> You have heard described between yesterday and today a lot of
> information. You have heard the roles of the FDA and DEA in risk
> management, benefits of clinical use of opioids, risks of misuse and
> abuse of opioids and data reflecting those areas, and you have heard
> about concerns around prescription opioid diversion.
>
> \[Slide\]
>
> We have heard general principles of risk management, examples from
> both non-opioids and opioid programs that already exist. Today we have
> heard about the abuse liability of hydromorphone, specific features of
> the risk management program that has already been started for
> Palladone, as well as some of the challenges associated with
> long-acting opioids and addiction.
>
> \[Slide\]
>
> I think the biggest concept that we have heard though is that there
> are all these challenges so the task at hand for today, one of the
> tasks at hand, will be, based on the discussion that we have had\--is
> the Palladone risk management program, as it has been defined, likely
> to result in safe use, limit the potential for abuse and misuse
> without limiting the access for appropriate patients. So, will it
> achieve the basic goals that have been set for it?
>
> \[Slide\]
>
> The challenges to risk management which are common to Palladone are
> common to all the modified-release opioids. I am going to go over a
> lot of these areas quickly because they have really been covered a
> number of times.
>
> While I am going to be reviewing what we think might be some of the
> limitations for this plan, I just also want to state that we should
> keep in mind that this represents one of the most detailed plans that
> has been established so far and it really represents I think one of
> the best efforts so far. So, we are going to discuss limitations but
> keep in mind that this is what we have to work with so far.
>
> \[Slide\]
>
> The approaches to meeting these challenges have also been discussed
> between yesterday and today in terms of the tools available and span
> these areas of education, surveillance and intervention.
>
> \[Slide\]
>
> These elements of risk communication and education have been
> incorporated into the Palladone plan. One of the questions though that
> this area raises is do we want to rely solely on the sponsors of these
> products to educate physicians? And, we need to think creatively about
> additional programs to help ensure that the physicians prescribing
> these products are fully informed about the risks as well as the
> benefits, and the proper approaches for treating patients with chronic
> pain with opioids.
>
> One of the examples for approaches for this has already been discussed
> somewhat, perhaps linking licensure for prescribing scheduled products
> with some type of demonstration of adequate knowledge.
>
> \[Slide\]
>
> The surveillance encompasses several areas we need to know about,
> exposure data, clinical use, drug abuse, adverse event data. A number
> of existing data sources have been incorporated into this risk
> management plan.
>
> \[Slide\]
>
> The National Prescription Audit from IMS Health and the National
> Disease and Therapeutic Index from IMS Health provide information on
> the prescriptions written and the patterns of treatment of disease
> encountered in office-based practice but these databases cannot tell
> us whether the prescribed drugs are used by the intended patients or
> if prescriptions were written appropriately. The patient tracking and
> analysis report tracks patients for the prescriptions filled by
> participating pharmacies so while we can get some longitudinal
> information, again, it is not designed to track non-medical use. DENS
> is another existing database incorporated into this program that I
> will discuss a little bit later.
>
> \[Slide\]
>
> The abuse data has also been described, sources of different
> information. I am going to discuss DAWN again in a moment. The
> National Household Survey, which has been retitled but it escapes me
> right now, is somewhat limited because it is self-reported. The Toxic
> Exposure Surveillance System is also somewhat limited because reports
> to poison control centers are more likely or somewhat likely to
> represent unintentional cases of exposure, accidental exposure, as
> well as some intentional exposure but it is not really set up to
> define abuse or set rates for abuse.
>
> \[Slide\]
>
> DAWN has been frequently considered for use as a numerator. We have a
> database that reflects events resulting in emergency room visits, or
> we also have the medical examiners\' cases. But DAWN does not
> distinguish between products for any given opioid. At least
> historically, this hasn\'t been true. There may be some changes to the
> system that will be helpful for this in the future. There are also
> some other anticipated changes in the reporting of the DAWN data and
> for the near future perhaps that is going to limit the availability of
> establishing trends using this information.
>
> \[Slide\]
>
> As described today, we have heard about the RADARS program and the
> data sources involved with that surveillance.
>
> \[Slide\]
>
> Some of the concerns with the Key Informant Network which, just to
> remind you, collects cases of abuse and addiction by survey from key
> informants knowledgeable about the emergence of drug abuse in their
> catchment area, includes addiction treatment specialists, pain
> management specialists, impaired health professional programs and
> other informants, but there is an uneven geographical distribution for
> the informants. About half are responding for each survey and it is
> not necessarily the same participants for each survey. Sites with high
> rates may be reflecting activity outside the three-digit zip code.
> This sounds like it is going to be addressed. Again, we have questions
> about the denominator, what to use with this information. Also
> important to note is that this is a non-random selection of
> informants.
>
> \[Slide\]
>
> The Drug Diversion study, based on law enforcement personnel working
> on prescription drug diversion, suffers somewhat from a small number
> of participants and a high turnover rate among those participants. The
> data collection is inconsistent. For instance, data on dosage usage is
> not collected consistently by each program or by some programs at all.
>
> \[Slide\]
>
> DENS, which is incorporated into RADARS but preexisted RADARS, also
> has some shortcomings. This is a program that is funded by the Office
> of National Drug Control Policy and the Center for Substance Abuse
> Treatment. Data is currently collected on five opioids. There are some
> limitations to the sampling, with a preponderance of urban areas. It
> is only covering adult treatment programs and we are concerned about
> non-adult abuse as well. These kinds of programs also suffer from high
> rates of staff turnover. These are all things that can impact on the
> usefulness of the information available.
>
> \[Slide\]
>
> The Poison Control Center study, similar to TESS, is going to be
> limited by the kind of information reported into the system. So, there
> may be an under-representation of the kinds of events we are looking
> for related to intentional abuse. It is useful information in terms of
> the concerns we have about unintended and accidental exposure.
>
> \[Slide\]
>
> We struggle\--what is the proper numerator? What is the right case
> definition? Should it be abuse, addiction, some combination with
> misuse, diversion, dealers, problem prescribers? We worry that the
> actual case definition might ultimately underestimate the incidence of
> some of these problems. As noted, we don\'t really know what is the
> best approach for creating a denominator. Patient exposure and
> prescription data don\'t report what is going on in terms of
> availability or what is happening to these products when people access
> them by means other than acceptable prescription writing. So, they may
> be underestimating exposure.
>
> Population in kilograms sold represents such a large number of
> individuals or product that it may not provide the sensitivity to
> changes in abuse or prescribing patterns that we may want for
> detecting signals early.
>
> \[Slide\]
>
> The sponsor has defined a signal detection level of at least five
> cases per 100,000 population in a three-digit zip code. Again, we just
> don\'t know what is the appropriate sensitivity that we should have
> for these programs.
>
> \[Slide\]
>
> Then, once we have information do we even know what are the
> appropriate comparators? How do we establish baseline when the systems
> become developed and available after problems develop, for instance,
> with OxyContin information or prospectively even with a product like
> Palladone? How do we establish a baseline against which to look at
> change? Then, how will discrepancies that are detected in the data be
> resolved? What I mean by ambiguous reporting responsibility is what
> will be the appropriate course of action associated with detection of
> signals from other sponsors\' products?
>
> \[Slide\]
>
> The arena of possible interventions is very interesting but, again, we
> don\'t know when to intervene, what interventions are necessary or
> most appropriate, and who should be doing this intervention. Should
> the company be responsible for correcting problems that are detected
> with this system?
>
> \[Slide\]
>
> So, again I raise for you the task at hand, and this is a little bit
> more formally presented based on the questions that have been
> developed for today\'s session. Based on the information that has been
> presented at this meeting, and taking into account your earlier
> discussion and deliberation about risk management plans for
> modified-release opioids, does the Palladone risk management plan,
> including its proposed labeling and indications, define a program that
> will likely result in safe use of the product and limit the potential
> for abuse and misuse of the product while assuring that appropriate
> patients are able to receive the medication? Thank you.
>
> **Open Public Hearing**
>
> DR. KATZ: Well, I guess our work is cut out for us but, luckily, we
> are going to the open public hearing now and we will be able to eat
> lunch before we tackle those thorny questions. So, are all open public
> hearing speakers available?
>
> I have to read that statement again that I read twice yesterday.
> Again, this statement or version of it is read prior to each of the
> open public hearings: Both the FDA and the public believe in a
> transparent process for information gathering and decision making. To
> ensure such transparency at the open public hearing session of the
> advisory committee meeting, FDA believes that it is important to
> understand the context of an individual\'s presentation. For this
> reason, FDA encourages you, the open public hearing speaker, at the
> beginning of your written or oral statement to advise the committee of
> any financial relationship that you may have with the sponsor, its
> product and, if known, its direct competitors. For example, this
> financial information may include the sponsor\'s payment of your
> travel, lodging or other expenses in connection with your attendance
> at the meeting. Likewise, FDA encourages you at the beginning of your
> statement to advise the committee if you do not have any such
> financial relationships. If you choose not to address this issue of
> financial relationships at the beginning of your statement, it will
> not preclude you from speaking.
>
> The first speaker is Khari LaMarca. Is Khari LaMarca here?
>
> \[No response\]
>
> Our next speaker is Dr. Tom Stinson. Because of the change in our
> schedule for today we have more time for public speakers. Public
> speakers will actually have ten minutes today and we will give you a
> two-minute yellow light prior to the end of your time, at which time
> the red light will come on.
>
> DR. STINSON: Thank you. My name is Tom Stinson. I am an
> anesthesiologist in Medford, Massachusetts. As far as I know, I have
> no conflicts of interest.
>
> Mr. Chairman, members of the committee, I have a few comments about an
> aspect of risk management that has only been alluded to in earlier
> testimony briefly, namely, the management of the legal risk to
> physicians who prescribe opioids to chronic non-cancer pain patients.
> As previous speakers have noted, there is an apparent increase in
> number of physicians who are being subjected to regulatory or criminal
> prosecution in connection with opioid prescribing. These actions are
> frequently based on legal standards which are vague and uncertain,
> incorporating such poorly defined terms as legitimate, adequate and
> professional.
>
> A well-formulated risk management plan for Palladone has the potential
> of providing a remedy for this problem by addressing physicians\'
> justified reluctance to use opioids of this sort based on fear of
> violating ill-defined legal rules and medical standards. To avoid
> perpetuation of this problem, any risk management plan for Palladone
> should be sufficiently detailed and well-defined, including definitive
> standards for documentation, so that compliance can be regarded by
> physicians as a reliable, safe haven for the prescribing of Palladone.
> Thank you.
>
> DR. KATZ: Thank you, Dr. Stinson. Would anyone from FDA care to
> address Dr. Stinson\'s question about whether it is even possible to
> include documentation standards or other aspects of the risk
> management program that would deal with this concern that physicians
> have about prescribing Palladone? Is that even a possibility and in
> what form could it be implemented?
>
> DR. MEYER: That is really much more along the lines of practice of
> medicine; it is not something that ordinarily FDA considers itself to
> have purview over.
>
> DR. KATZ: Dr. Van Zee, you are next.
>
> DR. VAN ZEE: My name is Dr. Art Van Zee. I am a general internist and
> practice primary care medicine in St. Charles, Virginia, which is a
> small coal mining town in southwest Virginia, where I have been for
> about the last 27, 28 years. I have no financial disclosures.
>
> I appreciate the opportunity to make comments today regarding risk
> management issues surrounding Palladone.
>
> \[Slide\]
>
> As an overview of where I am going with this talk, I would suggest to
> you that the information in the literature suggests that
> sustained-release opioids have no significant benefit over
> immediate-release opioids, save the convenience of b.i.d. or q.i.d.
> dosing.
>
> \[Slide\]
>
> I would suggest that the risks of sustained-release opioids are
> distinct and greater than immediate-release opioids. I would also
> suggest that one of the most important factors to consider in
> Palladone risk management is the way that this drug is marketed, and I
> will briefly spotlight the marketing of OxyContin.
>
> \[Slide\]
>
> These studies compared OxyContin with immediate-release oxycodone and
> essentially showed comparable efficacy and safety.
>
> \[Slide\]
>
> It is also of interest to look at the new drug approach for OxyContin,
> submitted by Purdue in 1995, and this was the medical review
> officer\'s conclusion at that time, who was Dr. Curtis Wright. He had
> suggested that the summary for safety was that OxyContin was
> equivalent to immediate-release oxycodone, with an adverse event
> profile that is as good as immediate release and would not allow a
> better claim.
>
> \[Slide\]
>
> He went on to conclude with a summary of efficacy, that OxyContin
> appeared to be a b.i.d. alternative to conventional q.i.d. oxycodone.
> Approval is recommended. Care should be taken to limit competitive
> promotion. This product has been shown to be as good as current
> therapy but has not been shown to have a significant advantage beyond
> reduction in frequency of dosing.
>
> I think Purdue Pharma, as a corporation, had confidence in Dr. Curtis
> Wright\'s professional capabilities and sometime subsequent to his
> work at the FDA, he was hired by Purdue and remains in their employee
> up to this year.
>
> \[Slide\]
>
> Other slides looking at sustained-release opioids have compared
> sustained-release morphine versus OxyContin and these have been
> comparable in efficacy and safety.
>
> \[Slide\]
>
> Immediate-release hydromorphone was compared to 12-hour
> sustained-release hydromorphone and is comparable in efficacy and
> safety.
>
> \[Slide\]
>
> And these are two studies in cancer patients, OxyContin versus
> sustained-release 12-hour hydromorphone, comparable in efficacy and
> safety in this study.
>
> \[Slide\]
>
> So, in summary, I would suggest that that information would show that
> immediate-release opioids and sustained-release opioids are clinically
> comparable in efficacy and safety if dosed appropriately.
> Sustained-release preparations appear comparable in efficacy and
> safety with the few studies that you have available to you comparing
> one to the other.
>
> \[Slide\]
>
> So, my summary of the benefits of sustained-release opioids would be
> that they certainly can carry some convenience of b.i.d. or daily
> dosing; certainly the convenience of less pills; and there is
> certainly a sub-segment of patients that are intolerant to other
> opioid preparations. All of us have these people in our practice and
> this may be a real benefit to them.
>
> \[Slide\]
>
> Let\'s talk a little bit about what the risk of sustained-release
> hydromorphone could be. Certainly the risk of addiction when taken
> exactly as prescribed is unknown. There have been some speculations on
> this but the risk is really unknown. We don\'t have any definite data
> on that. Five percent was a figure discussed today. If, indeed, it is
> five percent and you have a million people prescribed opioids for
> chronic, non-malignant pain and your iatrogenic addiction is 50,000
> people, that seems to me an enormous harm and you would have to weigh
> that against whatever benefits you could say were produced from your
> treatment.
>
> There is certainly an increased rate of addiction when used
> non-medically or recreationally. There are literally tens of thousands
> of new opioid addicts in central Appalachia that are there over the
> use and abuse of OxyContin. There is an unprecedented epidemic of IV
> drug use and hepatitis C that we have never seen before.
>
> Basically, the predominant story that I hear, and I have probably seen
> hundreds of young people that are OxyContin dependent, not the uniform
> story but the predominant story is that they had recreationally used
> Proxid and Lortab. This is how many young people party these days with
> beer and pills, and they certainly used those, snorted pills, for
> example Lortab at parties, were able to walk away from that and once
> they were exposed to OxyContin they were not able to do that and
> became rapidly addicted. People do not snort molecules or milligrams,
> they snort pills. If you do a 40 mg OxyContin at a party, it is going
> to be equivalent to doing eight Percocets and your risk of addiction
> is enormously increased. There is the risk of overdose and death with
> high potency dosing in one pill for these opioid-naive patients.
>
> \[Slide\]
>
> So, to continue on with looking at what the risks are of Palladone, I
> would say it would be relevant to get a brief overview with the
> promotion and marketing of OxyContin. As we have seen from information
> presented here today, the block-buster commercial success of OxyContin
> cannot be attributed to its superiority over other available opioid
> products, and I would suggest it had much more to do with the
> promotion and marketing.
>
> There were at least four cornerstones that were influential in the
> commercial success of OxyContin. One was the aggressive marketing for
> chronic non-malignant pain. There was aggressive marketing to primary
> care physicians. The risk of addiction for chronic non-cancer pain is
> certainly one of the major stumbling blocks that primary care
> physicians have in prescribing opioids for non-cancer pain, and Purdue
> Pharma has systematically trivialized the risk of addiction for
> chronic non-cancer pain.
>
> They use sophisticated marketing data to target and influence high
> opioid prescribing docs. Purdue obtained IMS Health marketing data
> which identified the opioid prescribing patterns of all physicians in
> the country. They then divided this from top to bottom in ten segments
> or deciles, if you will, with the highest opioid prescribing
> physicians down to the lowest. They then targeted their marketing
> energy on the top few deciles. This type of marketing data will
> reveal, I think, what physicians might have a larger proportion of
> chronic pain patients in their practice, but it also reveals which
> physicians are the most liberal prescribers of opioids and, in some
> cases, the least discriminate, if you will.
>
> This targeting consisted of much more frequent and intensive visits by
> the sales representatives. It also included targeted mailings with
> information and sometimes Internet detailing meant to influence
> prescribing.
>
> Purdue coupled this approach with a lucrative incentive plan for the
> sales representatives. One sales rep in Florida, a few years ago, made
> \$100,000 in bonus incentive pay over and above her \$50,000 salary
> because of the high OxyContin sales in her territory.
>
> \[Slide\]
>
> How does this marketing approach go from the paper to ground level?
> What does it look like on the ground? We looked at five state graphics
> yesterday. They were obtained through the ARCO system that detailed
> opioid prescribing down to the retail level.
>
> DR. KATZ: Dr. Van Zee, I have to ask you to wrap up your comments.
>
> \[Slide\]
>
> DR. VAN ZEE: Basically, this targeting of highest prescribing opioid
> physicians meant practically that physicians that had been high
> prescribers\--these are just selected counties\--of narcotics
> previously became high prescribers of OxyContin.
>
> \[Slide\]
>
> We talked yesterday about the regional differences in OxyContin
> prescribing and that it correlated with high availability, and these
> were the demographic areas of abuse. DR. KATZ: Concluding statement?
>
> DR. VAN ZEE: I would suggest that if the FDA\'s allowed indications
> for Palladone are the same and the marketing is the same as OxyContin,
> then we will almost certainly replicate the OxyContin abuse tragedy in
> proportion to its general availability.
>
> I would certainly support unrestricted use in cancer. I think it is
> most prudent to have restricted access to Palladone for chronic
> non-cancer pain. This could be made available through a compassionate
> use program.
>
> The concept mentioned yesterday of specialized DEA certification for
> prescribing Class II drugs is intriguing and needs to be explored.
> Thank you.
>
> DR. KATZ: Thank you, Dr. Van Zee. There was another public speaker,
> Khari LaMarca. Is that person here?
>
> \[No response\]
>
> Thank you. Let me just remind people on the advisory committee that it
> is not appropriate to discuss advisory committee issues during lunch,
> and we will resume the meeting at 1:30. Thanks.
>
> \[Whereupon, at 12:40 p.m., the proceedings were recessed for lunch,
> to resume at 1:40 p.m.\]
>
> [A F T E R N O O N S E S S I O N]{.underline}
>
> **Committee Discussion**
>
> DR. KATZ: This is the discussion portion of our meeting, the main
> discussion portion. If everyone around the table could pull out their
> questions, we are going to go more or less according to that list of
> questions.
>
> Let\'s start by finishing up with Roman numeral I and trying to
> address Dr. Dworkin\'s hanging question about the benefits of
> moderate-release opioids. That is a question that is still hanging in
> the air. Is there obvious relevance to understanding the risk/benefit
> potential for Palladone and other modified-release opioids?
>
> So, the last question to try to get at in Roman numeral I will be what
> is the evidence of benefit of modified-release opioids over
> immediate-release opioids? I will open it up for general discussion,
> but Dr. Strom\'s exhortation is still ringing in my ears about
> evidence. So, personal opinion is fine and I would love to hear the
> opinions of the experts around the table, but I just think people
> should flag their comments by what level of evidence they are
> referring to, and refer to particular clinical trials and such
> experiences if they can. Dr. Gillett, you are first.
>
> DR. GILLETT: On page ten of the slides this morning, how secure is the
> formulation from abuse if it is promoted as being possible to sprinkle
> it on food?
>
> DR. KATZ: That sounds like a very important question but I am going to
> table that for the moment because we will get to it in the risk
> management portion of the discussion. So, don\'t let me forget. Let\'s
> just return to that issue. What are the benefits that we can attest to
> about modified-release opioids over immediate-release opioids? Dr.
> Leiderman?
>
> DR. LEIDERMAN: Actually, could I just ask a question, perhaps a
> related question in a slightly different way? One of the things that I
> think we are trying to get at is who are appropriate patients for not
> just the modified release but for the high dose, high potency. We are
> talking about this very narrow group of drugs. We are not talking
> about all opioids. Who are appropriate patients? I think it has been
> suggested, because it has been raised in other risk management plans,
> who are appropriate prescribers?
>
> Then, a related question to who are the appropriate patients is how do
> we define chronic and persistent pain? For example, the JAMA paper
> that is included in your background information with Dr. Portner, as a
> co-author on persistent pain and chronic pain in a methadone patient
> population defined it operationally as chronic severe pain that
> persisted for more than six months or impaired function. So, I just
> want to put that out there.
>
> DR. KATZ: Fair enough. I want to get to this issue of evidence for
> modified-release opioids. Unless there has been a change over on the
> FDA side where that question is no longer perceived as being of
> interest, I am going to focus on that. The issue of patient selection
> and whether certain patient populations should not be permitted access
> to this drug we are going to get to in question number three. The
> issue of whether certain prescribers are more appropriate will also
> come up in question number three. The question of definition of
> persistent pain will come up in question two. So, don\'t let me forget
> those. I am going to try to stick to my agenda and at least get some
> questions answered.
>
> Finally, are there any opinions about whether modified-release opioids
> do have benefits or not over immediate-release opioids? Dr. Van Zee
> actually just gave us a lecture on that very subject. Would anybody
> care to add to the discussion? Dr. Cush?
>
> DR. CUSH: I think we have heard, I think convincingly, that there is
> no advantage.
>
> DR. KATZ: Are you including that there is no advantage of convenience
> or compliance?
>
> DR. CUSH: No, that is an advantage but as far as efficacy or safety, I
> don\'t think that that has been demonstrated. So, to me, compliance,
> as was stated, is one thing that is attractive about them.
>
> DR. KATZ: So, there is a compliance and convenience advantage. Again,
> in terms of level of evidence, are you reporting that from your own
> impression, experience, or is there data that you have in mind in
> making that assertion?
>
> DR. CUSH: Impression based on what I have been presented here, at this
> meeting.
>
> DR. KATZ: Because we have not actually seen data on convenience or
> compliance.
>
> DR. CUSH: No.
>
> DR. KATZ: Dr. Ciraulo, you are next.
>
> DR. CIRAULO: Thanks. I think at least one advantage would be the level
> serum concentrations that one achieves. I happen to believe that as
> the level rises there is a euphoric effect and then during the decline
> you do get withdrawal symptoms. Even if you have the same actual serum
> level you have more chance of withdrawal. So, the closer you get to a
> flat serum level of the drug, the better.
>
> Then, I would refer also to Dr. Kreek\'s lecture about the issue of
> tolerance. I know better for the benzodiazepines and she can talk
> about the products, but intermittent use is associated with higher
> tolerance so you are less likely to develop tolerance. I believe that
> is how I understood her lecture and I know that is the case for
> benzodiazepines.
>
> DR. KATZ: Right, so it sounds like you are saying that the flatter
> serum level profile may be an advantage because it is less likely to
> produce euphoria which, in turn, is less likely to produce addiction.
>
> DR. CIRAULO: Yes.
>
> DR. KATZ: So, that really would be more of a theoretical advantage,
> right? We didn\'t see any data that compared the two classes of agents
> with regard to euphoria or addiction.
>
> DR. CIRAULO: No, we didn\'t see that data but there are data in the
> literature that would suggest that that is true.
>
> DR. KATZ: Thank you. Other advantages of modified-release opioids? Dr.
> Shafer?
>
> DR. SHAFER: I am searching right now to see if I can actually give you
> the references off my laptop, but when transdermal fentanyl was
> initially developed, it was developed for postoperative pain control
> and it was only very late in the program that that was thought to be
> dangerous and it was switched to chronic pain control. There were a
> number of studies done on the transdermal fentanyl preparations
> examining the quality of the analgesia and the influence of that on
> patient recovery, and they were quite positive. Compared to the
> salutary pattern that you get with repeated IM or IV dosing, the
> continuous analgesia from fentanyl in the postoperative population was
> found to be highly preferable to patients. Now, I am not advocating
> that this be used in a postoperative setting but you want data and
> there is data in that entire study group, and there was a whole series
> of studies there showing that patients did better when they were
> provided continuous analgesia.
>
> DR. KATZ: Are you suggesting then that at this point in time one can
> consider improved analgesia in the postoperative setting an advantage
> of modified-release opioids?
>
> DR. SHAFER: Yes, but I don\'t extend that to say that I am advocating
> use of these in the postoperative setting but I am advocating that,
> yes, continuous analgesia is beneficial to patients I think in any
> setting.
>
> DR. KATZ: Other potential advantages of modified-release opioids? I
> think it is appropriate to hear from the sponsor if they can refer us
> to any clinical trials or other data that suggest advantages of a
> modified-release opioid preparation over an immediate release. I
> realize I am springing this on you. You can do it in five minutes if
> you like. Dr. Saini?
>
> DR. SAINI: The aging population of America and the people who are
> older, sometimes they get demented and they can\'t remember, and they
> are on a number of drugs. So, having a long-acting drug, this way they
> don\'t have to remember if they took the drug or not. If they have to
> just take one pill a day or take a fentanyl patch every three days, it
> makes sense. I don\'t have any data, but for aging people who have
> memory problems it is ease of convenience so it makes sense that a
> long-acting agent should be beneficial.
>
> DR. KATZ: I think the point that you make is worth emphasizing, that
> we shouldn\'t trivialize the importance of convenience or enhanced
> compliance since those are essential for achieving the benefits from
> any form of therapy. Dr. Aronson and Dr. Strom.
>
> DR. ARONSON: I think your question is quite profound. I wish to
> reframe it in the context of our intent rather than the risk. I have
> heard evidence that perhaps the risk of an addict going toward a
> sustained release for the benefit that that addict would have might be
> mitigated compared to a shorter-acting drug.
>
> Having said that, I wish to reemphasize that I am curious, as you, to
> know if there is any data that would suggest that this
> modified-release version of the drug is beneficial for the treatment
> of pain in non-malignant chronic moderate to severe conditions. I
> would defer to some of my colleagues with expertise in psychiatry to
> help me understand if there is any reason to think the opposite, that
> the trigger of pain itself might be a motive that we wish to have to
> take a drug and in that instance I am wondering if that is a good
> thing that we would be losing by using a longer-acting agent.
>
> DR. KATZ: So, you are suggesting the possibility that there might be
> an advantage to feeling your pain and responding to it with
> medication. Dr. Strom?
>
> DR. STROM: I know we don\'t have data on this but I want to emphasize
> the importance of it and my disappointment at the answers I am hearing
> because I don\'t buy convenience as a viable argument for a
> symptomatic drug. If you are dealing with an antihypertensive drug, it
> is a different situation but if somebody is in pain they will want to
> take the medication; if somebody is not in pain they won\'t want to
> take it.
>
> Now, I have heard from my pain colleagues for a few years that pain is
> better controlled at a lower dose if you maintain people pain free as
> opposed to having them go in and out of pain. To me, that is a very
> viable argument if there is data underlying it.
>
> It is clear that these formulations have greater risk associated with
> their use. I have heard two at least theoretical benefits, one being
> the one I just described and the other being, in fact, if they are
> less addicting for whatever reason. But if there is no data supporting
> either of those benefits and if there is substantial increased risk,
> and there is good reason to think there is increased risk from the
> sustained formulations, why in the world do we need them?
>
> DR. KATZ: Dr. Bril and Dr. Ciraulo.
>
> DR. BRIL: I guess it follows on to this a little bit, I am not sure,
> if I am the patient with chronic pain that I have had for months or
> years, that I want to feel my pain four times a day to make my
> physician feel better about giving me something that makes me feel
> better and pain free. Feeling my pain once a day is probably going to
> be enough.
>
> So, I don\'t really know data on responses in pain four times a day
> versus once a day dosing, I just do know that my patients prefer to be
> without their pain as much of the time as they can be, and that is
> just general, practical experience. I don\'t have numbers and
> percentages. So, I think that is a real advantage. Beyond the
> Alzheimer\'s theory, it is relieving pain in the patient who has come
> to you to have their pain relieved and not letting them have it as
> frequently that is necessary. So, I think those are real advantages
> that are inherent. Now, yes, I do know you would like epidemiologic
> data there.
>
> DR. STROM: If I can respond, you can take the second dose a little bit
> earlier and still not have the pain in between. Again, the convenience
> is not a reason to take the risk of the fact that you have high dose
> products that, when people abuse, they will die.
>
> DR. BRIL: This is an obsessive patient who remembers to take their
> pills spread out every single time. But if a person has pain relief
> and gets busy, then they are in the middle of whatever it is, then
> their pain comes back and they have to go and take their pain \[sic\]
> and wait again as opposed to just taking it once in the morning. So, I
> can see the rationale for once a day dosing, and it is more convenient
> to take the pill once a day than three, four times a day.
>
> DR. STROM: Again, this is symptomatic therapy. I am hoping I am wrong,
> and certainly what I have been taught by my pain people would say that
> I am wrong, but is there not the data, as I have been told before,
> that the total amount of narcotic necessary and the total level of
> control is better if you maintain someone pain free as opposed to wait
> until they are in pain first?
>
> DR. KATZ: I think what you are saying is very clear. You are saying
> that there is one potential advantage that people claim anecdotally,
> at least some people, that with a modified-release opioid you may be
> able to get away with lower doses and at least as good pain control,
> or some people say maybe better pain control at the same dose but you
> will believe that after you see data.
>
> The second point is that it would be attractive if these low-release
> formulations were less likely to produce addiction based on this less
> euphoria model, or whatever model it was, and you will believe that
> when you see data that demonstrates that. Dr. Ciraulo?
>
> DR. CIRAULO: I wanted to respond. I didn\'t want to be in the position
> of being the advocate; I was trying to do what the Chairman wanted us
> to do and find the positive aspects and not shift to the risk. I think
> I agree with you that there is substantial risk so I didn\'t want to
> leave the impression that I was saying that this was enough to make
> this worthwhile.
>
> DR. KATZ: That is the task at hand, which is to try enumerate the
> potential advantages and then try to determine to what extent they are
> supported by evidence. Dr. Baxter?
>
> DR. BAXTER: Yes, actually there is data available. The PCA pump data
> supports that continuous analgesia will result in less total amount
> use. So, there is data available. I am sorry, I can\'t tell you who
> and where.
>
> DR. KATZ: Actually, if I could just clarify that, there are a number
> of studies now comparing PCA where the patient controls the dose,
> small intermittent doses administered by the patient to fixed doses
> and to IM, etc. which showed advantages, but that is not continuous
> analgesia; that is actually small intermittent doses titrated by the
> patient, the opposite. Now, if you compare PCA with the constant
> continuous infusion provided by the machine to PCA by itself,
> generally the continuous infusion is disadvantageous and it tends to
> be associated with similar analgesia but more side effects. So, I want
> us to be very careful in making those extrapolations but I appreciate
> your point. What was the second thing?
>
> DR. BAXTER: The second point is when we are talking about situations
> where there are people who have histories of addiction who then have
> chronic pain syndromes, it has been my experience, and I don\'t know
> if there are any studies available, that when you use long-acting
> narcotics to address their pain needs, you have a better outcome
> basically because you don\'t develop that pain, take a drug, pain,
> take a drug\--that cycle, because the essence of addiction is to take
> a pill or take a drink and then take another and take another.
>
> DR. KATZ: Fair enough. Thanks. Dr. Haddox?
>
> DR. HADDOX: Yes, sir. I have four comments in response to the question
> that you sprang on us. The modified-release drugs that we are speaking
> about today are single-entity opioids. As a result, there is no
> co-analgesic which might have toxicity in patients who require larger
> doses. For instance, you are giving someone 40 mg of OxyContin twice a
> day as opposed to the equivalent amount of Percocet or Percodan you
> are avoiding the acetaminophen or the aspirin issue.
>
> Secondly, it is very hard to do these head-to-head studies because if
> you are looking to try and show convenience, for instance, you are
> sort of unblinded by the fact that you diminish that because even the
> person who is getting the dummy immediate release has to take it every
> four hours.
>
> There are two studies, however, that we think address the issue. One
> is Betty Farrell\'s comparing MS Contin versus MS IR in an open-label
> cancer study, the City of Hope, and what she was able to demonstrate
> was that there was an improved quality of life in the
> sustained-release group as measured by things such as impact of the
> pain on sleep disruption, on mood and relationship, the ability to
> interact with other significant people.
>
> Secondly, there is a randomized, controlled study by Scheville, in the
> literature, dealing with total knee replacement, looking at time in
> rehab following total knee replacement, comparing controlled-release
> oxycodone to immediate-release oxycodone in roughly equivalent doses,
> with the immediate release being p.r.n. versus the controlled release
> being on a fixed schedule. They were able to show that there was a
> faster return of range of motion in the controlled-release group and
> that they were discharged from rehab statistically significantly
> earlier.
>
> DR. KATZ: That is very helpful. Thank you very much. Dr. Storm?
>
> DR. STROM: Yes, just to follow-up because this is such a central
> issue, is there anybody else who has reviewed either of those papers?
> The fact that it is hard to do the study doesn\'t convince me and,
> because I don\'t think the issue of convenience is a central issue
> here, I think it could be done blinded. But even the unblinded study,
> if you are talking about Andrea Scheville, I know Andrea. She is about
> to enter our program to learn how to do research\--
>
> \[Laughter\]
>
> So, I don\'t know that study but it leaves me worried about it and I
> just want to be sure that somebody else, who is a pain expert, has
> seen these two studies, or FDA, and has some sense that those are
> reliable because this is obviously very central.
>
> DR. KATZ: Where is Dave Haddox? Oh, do you think you could get us
> those studies?
>
> DR. HADDOX: Sure.
>
> DR. KATZ: That would be great. Is anyone around the table able to
> answer Dr. Strom\'s question, having seen those studies? I, myself,
> haven\'t seen them, I am embarrassed to say so we will look forward to
> reviewing them. In any case, those two particular studies, one deals
> with a small population of cancer patients where I think the role of
> modified-release opioids\--I don\'t know anybody who questions their
> value. And the second\--
>
> DR. HERTZ: May I? I did actually review one study, I don\'t know if it
> was exactly the same one, looking at return of function in a rehab
> population following knee replacement and looking at modified-release
> oxycodone versus immediate release, and we actually found that the
> study didn\'t have merit. I don\'t know if it was exactly the same
> one. I can\'t recall the author but the one we reviewed was
> methodologically flawed and we didn\'t think that conclusions could be
> based on it.
>
> DR. KATZ: Well, I think the flavor of the discussion, and somebody
> chime\--Bob, did you have something to say?
>
> DR. DWORKIN: I think it needs to be said, not to muddy the waters, and
> to follow-up on what Dr. Strom was saying, I think certainly in our
> pain clinic, and I think this is sort of widespread experience, about
> a third of the patients getting OxyContin are taking it t.i.d. and not
> b.i.d., attenuating this convenience issue plus, of course, many of
> the patients on modified-release opioids are getting breakthrough.
> When you add in the patients getting t.i.d. rather than b.i.d. and the
> patients getting breakthrough, I don\'t know what to think about as I
> listen to this convenience argument. I have no data but I think it is
> a widespread sense that these aren\'t patients, at least in pain
> clinics and I don\'t know about general practice, who are taking only
> b.i.d. drugs.
>
> DR. KATZ: I will put you on the spot again and maybe the sponsor can
> help educate us there as well. Is there any data from marketing
> sources or any sources that looks at the median dose frequency or the
> proportion of patients taking different numbers of tablets, comparing
> those on controlled-release opioids versus those on immediate-release
> opioids?
>
> Well, I got them scurrying again. Let me say what I was going to say a
> minute ago, which is that it seems like the sense of what I am hearing
> is that there are a number of potential advantages to modified-release
> opioids, one, that potentially and some people feel anecdotally, one
> could possibly control the pain better at lower doses.
>
> Another advantage is that perhaps they are less addictive either by
> virtue of not producing as much euphoria or by not being associated
> with withdrawals or having reinforcing effects from a behavioral
> perspective, or any other variety of potential pathways.
>
> A third potential advantage that may be supported by a small study
> that we need to review is that perhaps patients can engage better in
> rehabilitation, at least after total knee replacement.
>
> Another potential advantage is a few of the quality of life parameters
> that Dr. Haddox mentioned for the cancer patients, reduced sleeping
> and improved social interaction I think was the other, again, in a
> small cancer population.
>
> It sounds like, at best, we have small randomized trials, and for some
> of these issues we have anecdotal evidence and that is it. That is my
> sense of what everyone has said so far. Dr. Haddox?
>
> DR. HADDOX: Can I make sure that I understand your question. You want
> to know if market research data indicated the frequency at which
> OxyContin was prescribed?
>
> DR. KATZ: No, my question was do people on controlled-release opioids
> take fewer doses per day than people on immediate-release opioids,
> fewer total number of pills, pill taking episodes per day?
>
> DR. HADDOX: I don\'t know the answer to that from a data standpoint,
> but since everyone else was talking anecdotes, I have some of those
> myself having treated a number of patients with this type of therapy
> using various long-acting drugs, and I think it varies quite a bit
> with the person. It varies with the population. The population that I
> saw at a tertiary referral center was probably not representative of
> the average pain population.
>
> We know from the 1999 survey that the American Pain Society and the
> American Academy of Pain Medicine did that 51 percent of the patients
> with chronic moderate to severe pain are being seen at the primary
> care level, not at the specialist level. I can tell you that even
> within my practice there was a great deal of variability. Some
> patients found that even though they had to take p.r.n. medicines
> because their pain was not constant throughout the day, taking a
> long-acting medicine at night got them through the night without any
> interruption but when they were up and active during the day they
> needed the p.r.n. but they didn\'t mind that because during the day
> they were awake anyway, for what that is worth.
>
> DR. KATZ: I appreciate it. Dr. Strom, a final comment on this issue?
>
> DR. STROM: Yes, I really have a question to the pain experts. Isn\'t
> it standard teaching that you should be on a basal long-acting
> analgesic plus rescue therapy as a standard and if, in fact, you are
> not requiring some rescue your basal dose may be too high?
>
> DR. KATZ: Who does pain education and would like to answer Dr.
> Strom\'s question about the standard?
>
> DR. SAINI: That is the standard teaching for acute pain management,
> not for chronic pain.
>
> DR. KATZ: I am surprised that you are asking about what people are
> educated since we have heard so many times today that education, if
> not based on data, can do more harm than good. That was very out of
> character for you I think, though we only met yesterday! Dr. Jenkins?
>
> \[Laughter\]
>
> DR. JENKINS: I would like to ask for you or the committee to
> characterize a little bit more about the level of evidence to support
> the purported benefit of reduced potential for addiction for the
> sustained-release products because that has obviously been a very hot
> topic, and I am concerned about the transcript of this meeting showing
> the advisory committee as saying that there is a reduced potential for
> addiction for modified-release or sustained-release opioids without
> some characterization of what is the level of evidence to support
> that. So, I would like to hear more quantification, if you can, of
> that level of evidence.
>
> DR. KATZ: Would anybody like to answer Dr. Jenkins\' question
> describing the level of evidence behind the relative predictive
> potential of long- versus short-acting opioids? Dr. Skipper?
>
> DR. SKIPPER: I would refer to the methadone data, that methadone is
> not a primary drug of choice and doesn\'t seem to cause addiction as
> commonly or as readily. The problem with the CR compounds is that they
> can be segregated and then they are not CR compounds. You know, as Dr.
> Kreek said, if there was intrinsically slow onset, and what-not, then
> I think it would be easier to make that case. But I am not confident
> in that at this point because we haven\'t had enough information to
> feel secure.
>
> DR. KATZ: Dr. Ciraulo?
>
> DR. CIRAULO: It is my feeling that the evidence is suggestive but
> certainly not anywhere close to being definitive. I think there are
> two issues. If you look at the rate of brain penetration and if, for
> instance, you have two different formulations, one that enters the
> brain more quickly and produces euphoria, and then you have an
> infusion that is slower, say, diazepam, the rate of euphoria is
> definitely lower with the same chemical compound.
>
> Now, I think we are mistaken if we believe that all opioids that are
> mu agonists act in the same manner. So, you know, when we talk about
> the level of absorption or the rise in the serum level or the drop in
> the serum level, that is only half the story. The other half is what
> is going on at the receptor level, which I think is quite complicated,
> as we heard from Dr. Kreek\'s presentation. But since I am the one who
> brought it up, I would say addiction is not the proper way to phrase
> that. I would say the rate of increase in the plasma level or the kind
> of plasma level has an influence on subjective effects such as
> euphoria or dysphoria related to withdrawal. To the extent that that
> is related to addictive behavior, then there is a relationship. I
> would not say that the evidence is very strong for the link to
> addictive behavior.
>
> DR. KATZ: Do any of our epidemiologists, Dr. Maxwell, FDA, anybody,
> feel that after reviewing the hundreds of slides of epidemiologic data
> that we have seen over the last day and a half, one can use that data
> to address the hypothesis that short-acting and long-acting opioids
> have a different potential to be associated with addiction? Dr.
> Leiderman?
>
> DR. LEIDERMAN: That is a bit of a big question. If I can answer sort
> of a narrower one since I don\'t think our SAMHSA epidemiologist
> colleagues are still here, I think, as we learned from the OxyContin
> experience it is very important to say this is a lesson for a lot of
> the parties involved, that the controlled-release formulation that had
> been thought to potentially significantly reduce risk of overdose,
> misuse, abuse and addiction turned out to be very readily violated.
> Thus, you have just higher dose of an immediate-release opioid.
> Basically, all of the ones we are talking about are shorter-acting
> opioids. Methadone is really I think the only long-acting drug and
> that is really not sort of on the table here; it is not being
> reformulated to my knowledge.
>
> DR. KATZ: I think it is fair to remind ourselves that we are really
> dealing with two separate problems. One is the diversion of
> modified-release opioids where the modified-release mechanism can be
> defeated at which point it becomes a high dose of an immediate-release
> opioid, and nobody is suggesting that that has a lower abuse
> potential, I don\'t think.
>
> Then the question Dr. Jenkins asked I think is in the setting of
> therapeutic use of opioids where one is prescribing to patients, is
> the prescription of a long-acting versus a short-acting opioid
> associated with a lesser likelihood of producing addiction?
>
> To summarize the committee\'s answer to your question, I think it is
> that the evidence that we have is very indirect. There is a study by
> Dan Prokoff, suggesting that if you talk to people in jail they will
> prefer short-acting opioids versus long-acting. There is the methadone
> maintenance experience which is an experience with a population of
> patients whose primary diagnosis is substance abuse where they seem to
> have resolution of their addictive behaviors on methadone. Are those
> pain patients? Probably between 30-60 percent of them are but, again,
> that is a very indirect source of evidence.
>
> We have evidence from other sorts of therapeutic agents and from
> opioids to suggest that a more rapid rise in serum level is associated
> with more euphoria. The relationship between that and addition is
> speculative. And, that is the summary of the evidence. Have I missed
> anything? Dr. Maxwell?
>
> DR. MAXWELL: Just very quickly, we can\'t separate out the other
> opioids but clearly something is going on with the treatment data and
> the emergency room data. I just want this in the record, that there
> has been a significant increase in both the emergency room and the
> treatment data, and we don\'t have even the \'91 and 92 data presented
> to us but something is happening.
>
> DR. KATZ: I think I heard Dr. Strom say, and other people seemed to
> nod their heads, wouldn\'t it be great if that were the case and
> wouldn\'t we love to see data showing that?
>
> I am prepared to leave question one. Does anyone on the FDA side have
> any more questions that I am not planning on covering down the line?
> If not, we will move on to question two and I will read the question:
> In response to reports of abuse/misuse of modified-release opioids,
> the FDA changed the indication for OxyContin and other
> modified-release opioids to, \"for the management of moderate to
> severe pain when a continuous, around-the-clock analgesic is needed
> for an extended period of time.\" Please comment on the
> appropriateness of this indication and provide any specific
> recommended changes that may further enhance the safe and effective
> use of these products.
>
> So, we can open it up for discussion on this issue, what people think
> about this label and could it be improved to make the use of these
> medications more safe or more effective. Dr. Crawford?
>
> DR. CRAWFORD: Thank you, Mr. Chairman. Earlier this morning Dr. Baxter
> raised the potential for consideration of inclusion in the labeling to
> say that there is a high risk for abuse that requires additional
> monitoring. I would like to put that back on the table, as well as
> expand on it.
>
> We have heard several times the fact that CIIs cannot be refilled and
> a new prescription per se is required by DEA for each new therapy
> course. However, we also heard that there are few limits on the
> dispensing on the amount of drugs, other than perhaps insurance
> coverage. So, while some give a 30-day supply or so, others might give
> a 90-day supply and, as we all know, there are other ways for
> clinicians to assist patients, or for whatever reason, to circumvent
> that by post-dating and other processes. So, I am wondering if also
> there should be consideration in the labeling of the need for routine
> periodic reassessment of therapy by the prescriber.
>
> DR. KATZ: So, as I am hearing it, the team of both of you has come up
> with the suggestion for the label that would include screening
> patients for their risk for negative outcomes of opioid therapy and
> having an enhanced monitoring system for such patients. The second
> half of your suggestion would be to recommend periodic reassessments
> of those patients as part of therapy.
>
> DR. CRAWFORD: Yes, except it wasn\'t a team because we followed
> instructions and we didn\'t talk about it at lunch.
>
> \[Laughter\]
>
> DR. KATZ: No, but by interaction here during the meeting. Does anyone
> have any comments about that suggestion? Dr. Baxter, any comments?
>
> DR. BAXTER: Yes, I think that it is important because the producer
> actually has a lot of material that is available to help prescribers,
> but my experience with residents and other providers is that if they
> don\'t have to do anything extra, they will not do it. So, I think
> that in the spirit of trying, I guess, to manage the risk even
> further, we should periodically review those individuals who are found
> to be at increased risk in the first place.
>
> DR. KATZ: Thank you. Dr. Bril?
>
> DR. BRIL: I think what I might like to see in something like this
> would be a better definition of extended period of time. What do you
> mean by that? We are talking about educating the prescribers and that
> is fairly open-ended. Perhaps that could be a little better defined.
>
> DR. KATZ: I think that sounds like an important question and I do want
> to make sure that we visit this point brought up by Dr. Crawford. What
> do people feel about whether it would improve the safety or improve
> the effectiveness of these treatments to expand this labeling
> statement to include recognition of patients who may be at higher
> risk, recommending enhanced monitoring for those patients and
> recommending frequent reassessments? Frequent reassessments, by the
> way, is present in every guideline for these opioids that has ever
> been put forth so I don\'t think that would be new but, certainly, the
> notion of screening patients at higher risk and having enhanced
> monitoring would be a step forward. What do people feel about that?
> Dr. Cush?
>
> DR. CUSH: I am all in favor of that. I was also thinking the same
> thing, as I said earlier. I think that to have it in the indications
> section is a bit awkward. It is currently in a black box and I agree
> with you, the way it is worded in the black box I think is a little
> too soft and doesn\'t slap you as it should that this is something
> that needs to be taken seriously as far as risk assessment and
> monitoring as an important part of the warning and use of these drugs,
> but to have it in the indications is a little bit awkward. If it could
> be succinctly put in there that marked severe chronic pain should have
> provided an appropriate risk assessment or risk benefit assessment at
> the outset, but if it is a little awkward if it isn\'t included in the
> front.
>
> Usually what goes into the indication, as was said earlier, is marked
> or severe, with or without functional impairment. Just to comment on
> that, we did review that issue at our analgesic and nonsteroidal
> meetings in the past, and setting that up as an outcome measure was a
> big problem for all the people because you have back pain you might be
> able to show improvement in function but if you have, say, cancer pain
> and someone is debilitated, and what-not, how are you going to show
> improvement in function? Everybody has functional impairment but
> whether you can improve it is another issue. So, I don\'t know if
> function should be in there but I do like this idea of putting a
> higher standard as far as the need for risk assessment and monitoring.
>
> DR. KATZ: Dr. Shafer, you were next and then Dr. Strom.
>
> DR. SHAFER: First, I also do agree with the suggestion of my two
> colleagues here on either side. Something that is missing from the
> OxyContin package insert that is present in the Palladone package
> insert is the statement that the long-acting drugs should not be the
> first-line therapy. In order to be consistent with that and also I
> think with things we have said around here, that we wonder if there is
> really evidence of efficacy\--well, if they aren\'t efficacious let
> the patient push you towards needing the drug\--I would suggest that
> also be applied to the OxyContin package insert, that it not be the
> first-line therapy but, rather, be used when immediate-release
> preparations have either proven that that opioid is the correct opioid
> available and that the pain itself is even responsive to opioids.
>
> DR. KATZ: Thank you. Dr. Strom?
>
> DR. STROM: Firstly, I would like to agree with Dr. Shafer\'s
> suggestion. Especially given the iffy data we heard earlier about
> benefit, I think that makes a lot of sense.
>
> In terms of the other suggestions, certainly including periodic
> reassessment makes sense. It is sort of motherhood and apple pie and
> no surprise that it is in every guideline.
>
> In terms of screening for risk assessment and monitoring, I am not
> agreeing or disagreeing but I am going to do my usual thing and ask
> for data. I think it is important to realize that any intervention has
> toxicities. You know, how valid is our ability to do risk assessment,
> and is monitoring useful? Because if we say to people they should do
> it and they falsely believe they are able to do it, it can lead them
> down the line of giving it to people who maybe shouldn\'t be given it,
> or be reassured about people who they shouldn\'t be reassured by.
>
> So, we haven\'t heard any data that I recall that shows that risk
> assessment is, in fact, well validated, well proven and if you do risk
> assessment and monitor people you will have better outcomes than if
> you don\'t. Given that we don\'t know if that is true\--I mean, if
> there are data on that, that is fine. If not, I would argue we
> shouldn\'t be including it, especially in the indication.
>
> DR. KATZ: So, you are asking two questions. One is do we have
> validated screening criteria and, number two, do we have evidence that
> enhanced monitoring in that subgroup is effective. Dr. Hertz?
>
> DR. HERTZ: Thanks. I just actually wanted to ask Dr. Shafer to
> clarify. I just didn\'t quite catch exactly what he said. Was the
> comment that OxyContin should not be used as first-line therapy? Do
> you feel that should be in the indication or actually somewhere in the
> label?
>
> DR. SHAFER: It shows up for Palladone in the black box warning, as I
> recall, and I think it probably should be in the same place for
> OxyContin. This would be consistent across the class of
> extended-release opioids and I think that actually makes good medical
> sense as well.
>
> DR. KATZ: So, let\'s return to Dr. Strom\'s question. We have heard a
> suggestion that has actually resonated through many of our sessions,
> that there are certain people who are at higher risk for negative
> outcomes of opioid therapy but that that enhanced risk can be
> mitigated through some appropriate monitoring system. Dr. Strom asked
> the question what is the evidence that we can identify which patients
> are at high risk and low risk and we can appropriately classify those
> patients, and then further evidence that any different way of
> approaching those patients reduces their risk. Would anyone like to
> take on Dr. Strom\'s question? Dr. Baxter, did I see your hand up?
>
> DR. BAXTER: No, you didn\'t and I will let my esteemed colleague
> handle this one.
>
> DR. KATZ: Dr. Skipper, go ahead.
>
> DR. SKIPPER: There is plenty of data on the CAGE questions, just four
> questions. You know those questions, right?
>
> DR. STROM: CAGE is just a way of measuring that somebody is an abuser.
> That doesn\'t predict they are going to abuse a drug you are about to
> put them on.
>
> DR. SKIPPER: But it is a screening tool that has been shown to be
> sensitive and fairly specific, and it is easy to administer. It takes
> one to two minutes. There are also other tests\--
>
> DR. KATZ: So, those are tests for the diagnosis of addiction\--
>
> DR. SKIPPER: Right, for substance abuse.
>
> DR. KATZ: Are you aware of any data that assesses the predictive value
> of responses to those questionnaires for the subsequent development of
> opioid addiction in patients being treated with opioids for chronic
> pain?
>
> DR. SKIPPER: No, but we do know that people that have the substance
> abuse problem would be at higher risk to be given these meds.
>
> DR. KATZ: How do we know that? What data are you referring to that can
> give us a sense of evidence-based comfort in that assertion, which I
> think we all feel is true, but Dr. Strom\'s question is what is the
> evidence.
>
> DR. SKIPPER: I will have to think about it and look into it but I am
> sure I can find something.
>
> I wanted to say one other thing about screening, and that is other
> high risk groups would be people with psychiatric problems, such as
> bipolar disorder\--
>
> DR. KATZ: Again, based on what data?
>
> DR. SKIPPER: There is plenty of data that shows that. The report to
> Congress on co-occurring disorders\--
>
> DR. STROM: Co-occurring is different.
>
> DR. SKIPPER: Well, I am saying that people with psychiatric disorders,
> a number of them, have a high risk of substance abuse.
>
> DR. KATZ: Let\'s move forward with that clarification. I think it is
> fair to say, and somebody can challenge me if I am wrong, that there
> is no data whatsoever on trying to classify patients with chronic pain
> being given opioids for their chronic pain in terms of whether they
> are at higher or lower risk for using them. The only study is one
> small retrospective study of 20 patients where we compared patients
> with and without histories of substance abuse for their subsequent
> development of destructive behavior on opioids and identified some
> risk factors. But that was one very small study and is still, to date,
> the only one on chronic pain.
>
> Unless anyone is aware of any other studies in patients with chronic
> pain predicting addiction when they are prescribed opioids, the next
> issue is, well, can we find indirect evidence from the world of
> addiction where we can look for risk factors for the development of
> opioid abuse in general, forgetting about chronic pain? I think that,
> Dr. Skipper, is what you were trying to get at, that is, can we
> analogize from the world of addiction.
>
> So, let me reframe the question then and say to our addictionology
> colleagues what are the risk factors for opioid abuse in the land of
> addiction? And, what evidence is there behind our assertion that those
> are risk factors? Dr. Ciraulo, would you care to take that on?
>
> DR. CIRAULO: Well, I just wanted to refer to Dr. Passik\'s talk
> yesterday. There are some references included in that, and I don\'t
> know if our pain colleagues are familiar with these articles about
> aberrant drug-taking behaviors and how our pain colleagues consider
> the quality of these articles. I haven\'t reviewed the original
> articles but, clearly, they point to probably more predictable and
> less predictable characteristics. It does cite studies of cancer in
> AIDS and I can speak to the standardized measures used in psychiatric
> diagnosis which are appropriate. I don\'t know if that data is hard
> enough but there was some presented here yesterday.
>
> DR. KATZ: Dr. Dworkin, did you have a comment?
>
> DR. DWORKIN: Well, my sense is that there really is no systematic
> prospective research addressing this question of risk factors for
> aberrant behaviors in chronic pain patients. So, then the question is
> can we extrapolate from risk factors in the general population for
> opioid abuse to this medically ill population? I am a little bit
> skeptical about that, especially if what we are talking about is
> adding it into the label. I mean, it seems to me if you are going to
> put in assessment of risk factors being necessary in a label, it
> should be based on the patients that the drug is indicated for, not an
> extrapolation from the general population. I could be wrong, but my
> sense is there are no reasonable prospective, systematic studies of
> risk factors in pain patients.
>
> DR. KATZ: Dr. Baxter?
>
> DR. BAXTER: Yes, I agree with that in the sense that I am hard-pressed
> to cite for you some studies that have been done. But, on the other
> hand, when I was referring to making an assessment I was talking about
> asking the question if a person has previously had problems with
> opiates in the sense of having abuse; if they have, in fact, had any
> problems in the past with other substances; and, as my colleague
> mentioned, having a history of psychiatric illness. All of these
> things are known to put people at a higher risk. So, if you have this
> type of information, well, then I think that would behoove the
> prescriber to have a heightened sense of awareness that the
> possibility is there and that it is more likely in those individuals
> than in people who answer no to those questions.
>
> DR. KATZ: So, we have a proposal that from personal experience,
> clinical judgment and from extrapolation from the general population
> from the world of addictionology we can put forth some probable risk
> factors that still would need ultimately verification in a chronic
> pain population, those being history of psychiatric illness, history
> of substance abuse and history of prescription opioid abuse being the
> three that you put forth. Any comments on the reasonableness of those
> criteria for flagging patients at high risk, even given the fact that
> our level of evidence is no longer at the clinical trial level? Dr.
> Bril?
>
> DR. BRIL: I would agree fully. I mean, clinical trials are great if we
> have them and prospective, randomized studies are wonderful but we
> still have to deal with the world as it is, and there are a lot of
> areas where we don\'t have grade A evidence. We still have to deal
> with the person. As long as you know what the level of evidence is you
> are dealing with, then you still have to approach the problem. I mean,
> yes, maybe there is a lot of research to be done but I think it is an
> eminently reasonable approach to trying to identify patients who are
> at higher risk.
>
> The issue yesterday and today\--and this is what I found exciting
> about Dr. Kreek\'s talk\--is that we really can\'t identify in a
> fail-safe manner those patients who will be tolerant, or dependent, or
> have changes in their mu receptor. Perhaps when we get the genetics of
> it worked out we will be able to do a profile and say this patient
> should not receive an opiate ever, or you may always have to give this
> patient this drug, and these patients are safe. But we are nowhere
> near that yet\--perhaps we are very near to it, I don\'t know but we
> are not there yet. So, in the meantime we still have to do something
> to try and be safe in our prescribing practices.
>
> DR. KATZ: Dr. Strom?
>
> DR. STROM: I am someone who lives in non-randomized data for a career.
> I agree with you completely from a clinical point of view. We are not
> making clinical recommendations now; we are making regulatory
> recommendations. Regulatory recommendations need to be made on the
> basis of science and shouldn\'t be made if there isn\'t adequate
> underlying science underlying it. That is not to say that clinically
> you shouldn\'t do what makes the most clinical sense but we shouldn\'t
> be making rules that people are going to get sued for if they don\'t
> follow them if there is no scientific basis underlying it. On top of
> that, any intervention, again, has bad side effects of its own. Unless
> we know what will improve things we shouldn\'t be requiring it.
>
> DR. KATZ: What we are trying to do is advise this division of the FDA
> as to what is a reasonable way for physicians to practice medicine,
> although it does verge into discussion on labeling, and then they go
> on and decide what is appropriate from a regulatory point of view.
>
> DR. STROM: I thought question number two is here is the labeling, how
> should we change it? And, our discussion was what should we put into
> the labeling.
>
> DR. KATZ: It is, and I can be corrected but I think our role is to
> provide clinical wisdom and insight and evidence of data that
> addressees the issue of the label, and they will decide how to write
> the label in the end. Would anyone from FDA care to comment on that?
>
> DR. MEYER: It is certainly true that the discussion today, whether
> science or opinion, is advisory to us and we greatly value both. It is
> very helpful for us to know when it is opinion and when it is data
> based, however.
>
> DR. KATZ: Dr. Skipper?
>
> DR. SKIPPER: It is already in the package insert, you know, that it
> shouldn\'t basically be used in people that have a risk of misuse,
> abuse or diversion.
>
> DR. KATZ: Could you read that language?
>
> DR. SKIPPER: This is proposed on page 32. It says, Palladone can be
> abused in a manner similar to other product agonists, legal or
> illicit. This should be considered when prescribing or dispensing
> Palladone in situations where the physician or pharmacist is concerned
> about increased risk of misuse, abuse or diversion.
>
> So, it makes only sense that since they are saying there is a risk
> that we should advise people to screen for those risks.
>
> DR. KATZ: Not to put words into Dr. Baxter\'s or Dr. Crawford\'s mouth
> but it sounds like that wording suggests that if, for whatever reason,
> you happen to develop a concern, then you might want to go in some
> direction and I think what you are saying is that your are
> recommending a more proactive screening process whereby each patient
> for whom the physician is considering that medication ought to be
> screened. Then, if they make it into the high risk category, whatever
> screening criteria the physician uses, they perhaps should be
> monitored differently.
>
> DR. SKIPPER: Yes, absolutely correct. You are great!
>
> \[Laughter\]
>
> DR. KATZ: Now, I haven\'t heard anyone say that that is unreasonable
> in terms of the clinical practice side, forgetting about writing a
> label for a second. I haven\'t heard anyone say that that does not
> represent good medical practice and that one ought to screen one\'s
> patients for whether they might be more high risk or low risk and
> consider a more proactive monitoring system for those that may be at
> higher risk, even given the uncertainties in both the categorization
> as well as the efficacy of the monitoring. Does anybody feel that that
> is not a good way of using these medications? Dr. Cush?
>
> DR. CUSH: Well, I would make the suggestion that makes you want to
> argue with me, that is, if we were to have a proviso asking for some
> risk assessment in there, I would suggest that when these
> prescriptions are being written a one-page form goes out with the
> prescription which is a risk assessment. Some of this is taken from
> Dr. Passik\'s presentation from yesterday which I thought very good,
> but a risk assessment, some goal setting and some outcome measures. It
> is a one-page thing. It sort of indicates that some discussions went
> on between the physician and the patient about risks and concerns and
> achievable goals, and that can be part of a restricted access system
> which could be part of a database that is collected over time.
>
> Going back to Dr. Strom\'s point which I agree with, indications
> should have some rigid evidence-based principles behind them, and I
> would ask him to comment if he thinks this is wrong but I think what
> we heard yesterday and today is that there is a real need here, a real
> concern about abuse potential. Based on what we see, we don\'t know a
> lot about what is happening and the mechanisms behind it and, hence,
> there is a large area of study that is needed. Without doing something
> proactively in the form of labeling we are reliant upon who to do
> this.
>
> DR. KATZ: Actually, it may interest the group that there is a
> validation study that is ongoing right now to develop a self-report
> questionnaire that will screen patients for high risk and low risk for
> prescription opioid use. So, hopefully, that questionnaire will be
> available in nine months, or something like that. Dr. Rose and Dr.
> Strom and then I am changing the subject.
>
> DR. ROSE: What I would like to suggest is that we shouldn\'t say that
> the physician should do their own mental screening and then treat
> those patients that they suspect might be at high risk for abuse in
> one way and not treat the others in that same way. I believe that all
> patients should be treated the same, much the same as we are doing in
> emergency rooms and screening everyone for domestic violence rather
> than just saying, well, this person doesn\'t look like a victim of
> domestic violence. I think you have to treat all patients the same and
> you have to have a level of concern for everyone in the same manner.
> Then, once you have assessed everyone, then you can make your
> decision.
>
> DR. KATZ: Dr. Strom?
>
> DR. STROM: Yes, I agree. Again going back, I think any intervention
> has negative side effects and if you reassure people that these are
> people you don\'t need to worry about and you are reassuring them
> incorrectly, then you potentially increase risk.
>
> In terms of the other question that I was asked about the specifics of
> the risk management plan and having a form for use with everybody,
> that would be used with everybody, and I am much more comfortable with
> something like that that is used for everybody and we will presumably
> talk later on about the specifics. I still think in that kind of
> recommendation in anything we think about as we talk about the risk
> management plan, remember that these plans have side effects of their
> own. They will shift people to other drugs. People will not get
> access\--the more we put into the plan, the less access patients will
> have to the drugs. Maybe if they don\'t work well that is appropriate
> but if they have unique benefit it may be appropriate. But that is a
> different question and we need to keep that kind of thing in mind.
>
> I think it is very important to differentiate between clinical
> thinking, which you apply to an individual patient at hand and what
> you would do from a system point of view, which is being applied to a
> population because you have the balloon phenomenon, you squeeze here
> and it expands somewhere else. When you apply any kind of intervention
> it has side effects and we need to think clearly about what those
> interventions, therefore, should be.
>
> DR. KATZ: Did I hear you say that rather than classifying patients
> into high/low risk based on criteria that are not validated and just
> have an enhanced monitoring system for the putatively high risk ones,
> you would propose an enhanced monitoring system for everybody?
>
> DR. STROM: I would propose an enhanced monitoring system for everybody
> in studies to find out what real risk factors are. Again, a key
> difference in clinical decisions and regulatory and population
> decisions is that in the clinical situation you are forced to act in
> the absence of data; from a regulatory point of view, we shouldn\'t be
> recommending actions unless there are data that we know that the
> actions will make things better rather than worse.
>
> DR. KATZ: I am going to change the subject slightly, still keeping
> within question number two. One of the aspects of this statement that
> is put down here in question number two is for the management of
> moderate to severe pain. Nobody commented specifically on whether they
> felt that moderate to severe pain was an appropriate entrance
> criterion for appropriate use or whether that should be just severe,
> or whether it should be mild, moderate and severe, or whether we
> shouldn\'t mention pain intensity at all. Does anybody have any
> comments on that aspect of the label? Dr. Gillett?
>
> DR. GILLETT: In particular, I wanted to underline the functionality
> definition that was supplied yesterday, and I can\'t remember by whom,
> but the scale becomes an objective scale in terms of functionality
> whereas a subjective scale in terms of pain relief and so forth. I
> think that anything we can do to get into a two-way measure would be a
> benefit to the patient and to the provider.
>
> DR. KATZ: Dr. Strom?
>
> DR. STROM: I want to echo that. I certainly wouldn\'t restrict this to
> just severe pain. I think that pain practitioners are very used to
> thinking about a visual analog scale and measures of moderate to
> severe pain. But, as you all well know, the same person will rate some
> people\'s pain sometimes mild; sometimes moderate; sometimes severe.
> So, the actual use of the scale is totally arbitrary.
>
> I think what matters more is that the pain is severe enough to cause
> functional impairment and that you have tried other alternatives and
> the other alternatives haven\'t worked. I guess what I am talking
> myself into is that I would remove the issue of severity of pain
> completely and talk in terms of pain severity enough to impair
> functionality after having tried other alternatives and it didn\'t
> work.
>
> DR. KATZ: So, if I have a severe pain that is seven out of ten on a
> zero to ten scale, severe in intensity, but I am still able to get
> through and function, which is actually not such a bad description of
> my present condition right now\--
>
> \[Laughter\]
>
> \--you wouldn\'t let me take opioids?
>
> DR. STROM: If it is not impairing your function one could argue is it
> severe? Again, it leaves a lot of vagueness in the definition of
> function.
>
> DR. KATZ: Just to be absolutely clear, pain intensity is a
> well-validated construct and there are, you know, fifty years of data
> on the validity of pain intensity as a construct, and one way of
> measuring pain intensity is with a verbal categorical scale that
> includes descriptors such as mild, moderate and severe. Are you
> suggesting throwing out that paradigm?
>
> DR. STROM: I am suggesting, (a) it is a lot less well validated\--and
> John Farrow who some of you know worked with me is showing that\--than
> people think and, (b) that primary care docs, who are the ones who are
> prescribing most or a large proportion of this medicine, are not
> giving visual analog scales and they don\'t know what moderate to
> severe pain is in the same context. They do know that if patients have
> enough pain it is interfering with their function.
>
> DR. KATZ: So, your suggestion remains replacing pain intensity as the
> entrance criterion with the functional impairment?
>
> DR. STROM: From an indication point of view, not research-wise. Again,
> you know, I am not saying that research-wise but from an indication
> point of view.
>
> DR. KATZ: I think it would be appropriate to give Laura Nagel from
> DEA, since her group put forth removing moderate as a suggestion, a
> chance to comment on their reasoning behind that proposal.
>
> MS. NAGEL: Candidly, we follow very closely what was just put forward.
> It was the question of what is moderate and what is severe, and does
> everybody understand that to be the same, and when is it appropriate
> as a first-line or second-line? I am personally thoroughly enjoying
> the conversation and would very much follow the functionality
> statement. If I understood properly, you would still be using severe
> and moderate but what you would be doing is tying those same concepts
> to functionality, which might make it easier for non-specialists to
> follow. That is what we were trying to get to when we brought these
> up, that is, a term that would be understood by the generalist and
> understood better by citizens also as to what it means, and still
> using the scales and having it not necessarily be the first-line of
> defense as well.
>
> DR. KATZ: So, you are endorsing the idea of eliminating the subjective
> pain intensity rating from the entrance criterion but replacing it
> with a patient self-report of impairment of function, to be endorsed
> by a physician?
>
> MS. NAGEL: Yes.
>
> DR. KATZ: Dr. Meyer?
>
> DR. MEYER: Maybe this is turning the tables on Dr. Strom, what data do
> we have to suggest that\--
>
> \[Laughter\]
>
> \--I am serious, that a physician understands the subjective
> self-report of impairment of function better than they understand a
> report of mild, moderate or severe pain?
>
> DR. STROM: I think your question is very legitimate. I don\'t think
> the physician understands either of them very well. I think the
> difference is that we are dealing with symptomatic treatment and what
> matters is what the patient reports. I think an arbitrary definition
> of moderate or severe is arbitrary and what really matters is\--you
> know, the goal here is to relieve symptoms and does the patient have
> pain severe enough that they need this therapy and other therapy
> hasn\'t relieved it. That is a question of functionality. That is just
> a question of English in a way that a patient would understand. So, I
> am not looking here to target the physician. I think the moderate to
> severe targets the pain physician; it doesn\'t target either the
> primary care physician or the patient. I am looking to target the
> patient because ultimately the only way to find out if somebody has
> pain is to ask the patient.
>
> DR. KATZ: Dr. Dworkin?
>
> DR. DWORKIN: I couldn\'t disagree with Dr. Strom more because it is
> the simple fact that function is the slipperiest concept in the whole
> chronic pain world. How do you compare function in a 35-year old,
> single mother who is employed, with fibromyalgia, and a 75-year old
> retired quadriplegic who has spinal cord injury pain? If I knew the
> answer to that, I would know a lot more than I think any of us know in
> the chronic pain world right now. I completely agree with Nat that,
> you know, a zero to ten scale or none, mild, moderate or severe pain
> scale has a lot more weight of reliability, validity, responsiveness
> evidence base behind it than anything any of us could come up with in
> the next five years regarding function. I rest my case.
>
> DR. KATZ: Dr. Bril and then Dr. Strom.
>
> DR. BRIL: I guess my question also is what is the real purpose of the
> functionality? Pain is a patient symptom from none to the most severe
> and the patient really is the one who has to report and you assess
> your efficacy on what they are doing. Is the functionality reassuring
> the physician more because you feel better? If the patient doesn\'t
> have pain, they are not at all impaired with their function so that
> really validates the fact that they don\'t have pain? Whereas, if they
> say they have severe pain but they are still working, then they really
> don\'t have such severe pain so you are putting your judgment on their
> pain again?
>
> So, again, who is making the decision about the patient\'s pain and
> the patient\'s pain relief? Is it the patient or the physician? I
> think if it is the patient, then VAS which has been used in a lot of
> scales is quite good, and most people really know what mild, moderate
> and severe is through use if they are using that. Whereas, impaired
> function, for the reasons stated, can be very, very difficult and I
> think isn\'t any more validated. I mean, I don\'t really see that it
> is validated in this field at all.
>
> DR. KATZ: Dr. Jenkins?
>
> DR. JENKINS: I think this is a very good discussion and this is
> exactly what we need to hear because, as you know, we have been
> hearing advice from various parties that the moderate to severe\--the
> moderate part of that indication is a significant problem and there
> are those who have suggested that eliminating the moderate from the
> indication and limiting this to severe pain might actually lead to
> less prescribing. There has been the hypothesis that less prescribing
> means less drug that is out there with potential to be diverted,
> misused or abused. So, it is very important for us to hear this
> discussion so that we can understand the committee\'s views on what we
> should be doing in this regard.
>
> A little bit challenging some of what Dr. Strom has said, we are a
> science-based regulatory agency but that doesn\'t mean that we always
> rely just on randomized, controlled clinical trials to make our
> regulatory decisions. An example I would give here for putting the
> indication for opioids into our risk management concept is that I
> don\'t think there is any doubt that if you studied patients with mild
> chronic pain and treated them with a modified-release opioid I don\'t
> think there is any doubt that you would not find the drug to be
> effective. But we would not feel comfortable in the risk/benefit
> analysis recommending modified-release, high dose opioids for patients
> with mild chronic pain.
>
> So, putting this into a risk management perspective, I think it is
> very interesting and important for us to hear from the members of the
> committee about that moderate pain. I don\'t think there has been any
> suggestion from anyone that we should change the indication with
> regard to severe pain. The congressman who testified yesterday\--I
> think everyone I have ever encountered with this has said we view this
> as a legitimate and valuable drug for people with severe pain, but
> there are some who have questioned whether this really is needed or
> necessary or has a favorable risk/benefit balance for patients with
> moderate chronic pain. And, I am not advocating the position one way
> or the other; I am just trying to make sure that the committee
> understands the issues and gives us your answer in a risk management
> concept.
>
> Clearly, these drugs are effective in relieving patients with moderate
> chronic pain. The question we are trying to get from you is, is it
> appropriate that we indicate these drugs for moderate chronic pain,
> given their risk. So, you really need to look at this indication
> question as not simply what have the clinical trials proven to be the
> case because we have to go beyond that when we do our risk/benefit
> analysis. So, we really are interested in hearing what your
> risk/benefit equation analysis for moderate chronic pain is.
>
> DR. KATZ: Let\'s focus on that specific question then, and the
> specific question on the table right now is what is the risk/benefit
> analysis for the use of modified-release opioids for the treatment of
> chronic pain that is moderate in intensity? Dr. Shafer? I am starting
> my list all over again so if you want to talk, raise your hand again.
>
> DR. SHAFER: I would absolutely leave moderate on there, just to answer
> your question bluntly. I am concerned that taking the word moderate
> off would be an invitation to prosecution by the DEA, and my DEA
> colleagues have assured me that it would not be used that way but,
> nonetheless, as a clinician I may well interpret it that way and it
> might, I think, significantly restrict access.
>
> I am uncomfortable with people with moderate pain having to beg for
> adequate analgesia, and the diverters I think are not going to say,
> \"well gee, it\'s only moderate pain so my pain\'s just not enough. I
> suspect the diverters, although, again, I don\'t have data on this nor
> will there ever be data on this, but I think we can know things from
> reasonable extrapolation and diverters are very likely to be dissuaded
> by limiting it to moderate \[sic\] use because somebody\'s pain will
> just be a whole lot worse because it was fabricated at the outset. So,
> I would very much be against removing moderate. I think that it would
> actually be a significant restriction for use by clinicians. I would
> interpret it that way.
>
> DR. KATZ: And from a therapeutic perspective, it sounds like you are
> also saying that the risk/benefit analysis of using opioids in this
> population is favorable.
>
> DR. STROM: Well, you know, we have a lot of data presented even by Dr.
> Van Zee who got up there and said it certainly is no worse. And the
> safety studies, and there was a safety aspect to that, said it is no
> worse. So, I don\'t see a problem.
>
> DR. KATZ: Other comments on this issue? Dr. Wlody, you are next.
>
> DR. WLODY: I would like to make two points, again not necessarily
> based on evidence but opinion. First of all, when you are talking
> about moderate pain I think almost by definition you are talking about
> people who may have failed on NSAIDs at this point and then what is
> left other than opioids, either controlled release or immediate
> release, which is a separate issue? Certainly, in this group of
> patients, you know, I am not sure what the alternative is at that
> point.
>
> Second and sort of philosophical, you know, if we are talking about
> what a big problem untreated pain is in this country, we are not
> talking about untreated severe pain. I think that is recognized. We
> are not talking about untreated mild pain; we are talking about this
> large group of patients with untreated moderate pain and I think, you
> know, we have to provide the mechanism for treating these people
> effectively.
>
> DR. KATZ: Dr. Bril, you were next and Dr. Rose.
>
> DR. BRIL: I wouldn\'t remove the word moderate either. You know,
> patients with mild pain don\'t really want anything; they are happy to
> live with it quite often. When you talk about side effects of a drug
> they say, \"oh, no, it\'s not that bad.\" So mild is no problem at
> all. It is moderate where patients really need relief, and in the
> chronic pain conditions I deal with the agents that I have available
> to me are not universally effective or universally tolerated, no
> matter what they are, whether they are antidepressants or
> anticonvulsants which I tend to use first; I tend to go to the
> adjuvant analgesics. So, I would not wish another therapeutic avenue
> to be closed to me because there are a lot of patients there who still
> don\'t have relief and who need this option and you would be depriving
> them of this potential relief. That is not to say I think every
> patient responds to either short- or long-acting opiates either. I
> mean, there is still an unmet need.
>
> Moderate though is the level where a lot of my patients are willing to
> accept the risk of side effects in order to obtain relief. Moderate is
> really quite a marked level of pain for them, as well as severe, so I
> would not remove moderate.
>
> DR. KATZ: So, it sounds like what we are hearing is that restricting
> the use of these medications to just individuals with moderate \[sic\]
> pain would worsen the under-treatment of the pain problem and may or
> may not have an effect on reducing the diversion or abuse of this.
>
> \[Comment from the audience\]
>
> DR. KATZ: Oh, did I say the wrong thing? Thank you.
>
> I would like to move on unless there are any comments. Unless there
> has been some gross misapprehension of what the committee thinks, I
> would like to move on to the next issue.
>
> DR. JENKINS: Dr. Katz\--
>
> DR. KATZ: Go ahead.
>
> DR. JENKINS: Does anyone on the committee not agree with the proviso
> that the indication moderate to severe chronic pain with all the other
> conditions that are in the labeling or that you have suggested\--does
> anyone not agree that that is the appropriate indication for this
> drug? Is anyone in favor of severe only?
>
> DR. KATZ: Should we go around and see what people think?
>
> DR. JENKINS: Sure.
>
> DR. KATZ: Let\'s do that then just to be sure everyone has had their
> chance to respond. Let\'s go round the table and everyone can take
> half a minute and let us know what they think about the issue of
> moderate to severe and, if it should be modified, in what way should
> it be modified and why. Where should we start? I guess, Dr. Crawford,
> you are the first regular member.
>
> DR. CRAWFORD: I support moderate to severe for the reasons already
> articulated.
>
> DR. KATZ: Dr. Shafer?
>
> DR. SHAFER: I support moderate to severe.
>
> DR. KATZ: Dr. Baxter?
>
> DR. BAXTER: I support moderate to severe.
>
> DR. KATZ: Dr. Gardner?
>
> DR. GARDNER: I support moderate to severe.
>
> DR. KATZ: Dr. Aronson?
>
> DR. ARONSON: I support moderate to severe but I wish to speak to that
> a little bit further. I also recognize that the concern is
> accessibility and availability and that if we do support, as a
> committee, moderate to severe the likelihood is that there will be
> more available and more accessible drug.
>
> Having said that, I would like to turn back to the recommendation, I
> thought a very elegant recommendation that spoke to the labeling
> having a requirement to ask physicians to behave in a way that we all
> would perceive\--evidence not withstanding, we all would perceive to
> be the best way for physicians to behave, which is to take a history
> and elicit those risk factors in those patients that we believe would
> potentially be diverters. It serves all good. I think it is very hard
> to find the risk in that, again evidence not withstanding. I think the
> benefits of that far outweigh the risks, and I think if we are to say
> moderate to severe we ought to do that with the caveat that we are
> working with a heightened sensitivity that we have to police ourselves
> perhaps more than we would otherwise.
>
> DR. KATZ: You favor leaving moderate to severe and adding language to
> the label that encourages enhanced management of high risk patients.
>
> DR. ARONSON: Yes.
>
> DR. KATZ: Thank you. Dr. Saini?
>
> DR. SAINI: Moderate to severe, leave it the way it is written here.
>
> DR. KATZ: Dr. Kahana?
>
> DR KAHANA: I also would leave it as moderate to severe but I would
> want to reemphasize the point brought up earlier by Dr. Shafer that
> these patients should have failed immediate-release treatment first
> because that at least would reduce the number perhaps\--there are no
> data but perhaps it would reduce the number of prescriptions available
> for the sustained-release products and I think they really are a
> significant risk. I am not sure that anything we do to reduce
> availability by restricting physicians, however, is going to change
> what happens on the streets. I think we all have to recognize that. We
> just don\'t have any information.
>
> DR. KATZ: Dr. Bril?
>
> DR. BRIL: Moderate to severe.
>
> DR. KATZ: Dr. Rose?
>
> DR. ROSE: Yes, I am in favor of the moderate to severe and I was
> planning to make that comment also that previously\--I think it was
> Dr. Wlody who said something about patients failing nonsteoridals and
> going on to this drug, this is not appropriate, and all of the other
> material that we have about Palladone indicates that the patient needs
> to have already been on opioids on high doses and that this would be a
> conversion to the longer-acting drugs. So, I am in favor of the
> moderate to severe with the understanding that Dr. Kahana just
> verbalized about having failed other therapy.
>
> DR. WLODY: I favor retaining moderate to severe.
>
> DR. DWORKIN: I am comfortable with moderate to severe, uncomfortable
> with recommending assessment of any risk factors unless they are
> replicated and potent, and I don\'t think we have any, and I am also
> uncomfortable with limiting it to people who failed IR. Moderate to
> severe is fine.
>
> DR. CUSH: I am only in favor of severe but with the proviso that it
> could be worded as medication for chronic severe pain, or marked pain
> or severe pain, or moderately severe pain that impairs function, the
> reason being that in a primary care doctor\'s office and in my
> rheumatology office and in a pain doctor\'s office we all see a lot of
> moderate to severe pain. I would not like to see as many Class II
> drugs being written in a primary care doctor\'s office and I should be
> writing a whole lot less than is being done in a pain specialty
> office. So, I worry about the moderate being abused by a large segment
> of the prescribing population and for that reason I think severe
> should be on there. Again, pain with functional implications could be
> useful but that assumes that function is modifiable and it may not
> always be so. So, that is why severe pain or marked pain with
> functional impairment.
>
> DR. KATZ: Thank you. Dr. Bobek?
>
> DR. BOBEK: I support moderate to severe as well, and the package
> insert change that was recommended as well about it not being the
> first-line opioid choice.
>
> DR. KATZ: Thank you. Dr. Skipper?
>
> DR. SKIPPER: Because these drugs, or at least OxyContin, appear to
> recruit new addicts and cause deaths, and because there is no good
> evidence that the CR drugs are better than the IR drugs for
> controlling moderate pain and there are other options for people with
> moderate pain, I would say severe pain and add the limitation in
> function.
>
> DR. KATZ: Thank you. Dr. Ciraulo?
>
> DR. CIRAULO: I would favor severe as well for the reasons that have
> been mentioned. I think that one of the risks that we haven\'t talked
> about the past hour or so is a public health risk, and I think
> clinical experience with other agents really makes this a high risk
> for diversion and the consequences of diversion are going to be
> disastrous, and I think this should be reserved for severe.
>
> DR. KATZ: Thank you. Dr. Maxwell?
>
> DR. MAXWELL: Severe and, again, I am very concerned, and maybe it is
> my lack of knowledge, but I haven\'t heard evidence of why we need
> another drug like this right now. I am very worried about the damage
> that we could see if it is out and gets mishandled as OxyContin was.
> If it comes on market and it is well controlled and we don\'t have
> this kind of diversion, then I think it is appropriate to go back,
> after there is more data coming in, and perhaps consider adding on
> moderate but right now I am really opposed to this going on the
> market.
>
> DR. KATZ: Thank you. Dr. Strom?
>
> DR. STROM: I would not restrict it to severe, and the main reason is I
> think there are people who have moderate pain and significant
> impairment of function, not functional status as measured by a scale
> but there are things they want to do that they can\'t do because of
> pain and I think they should have access to these drugs. I think it
> should be specified as second-line drugs, that people should be tried
> on the milder drugs first.
>
> DR. KATZ: Dr. Gillett?
>
> DR. GILLETT: I agree with Dr. Strom. My point is that you can\'t
> calibrate yourself and develop a quantitative basis for any risk
> assessment on this. The nurse walks up to you and says how are you
> feeling today? You pause and you don\'t know what you are talking
> about because you don\'t have a pH meter for your pain scale. I just
> think that we need to have something like severe impairment in order
> to use a chemical like this.
>
> DR. KATZ: Dr. McLeskey?
>
> DR. MCLESKEY: Thank you, Nat. I think from an industry perspective we
> would obviously support the broader use of moderate and severe pain.
> If I could also respond though to the issue that Dr. Aronson raised
> just a moment ago about heightened sensitivity and the other issues of
> maybe enhanced screening and monitoring that have been raised
> previously as well, I just wanted to comment, and this will probably
> resonate with other topics that you will be discussing later in this
> session, that that would represent a hurdle and it might be a hurdle
> for clinicians that ought to be placed. If it is, as we consider all
> these ideas, I would just like for the clinicians especially on this
> committee to comment on is it too onerous a hurdle or is it something
> that would be acceptable.
>
> I would also like to plant the seed that as we apply those kinds of
> strategies it might actually be something, if it were specific and
> relatively easy for a clinician to accomplish them, that in fact it
> might be reassuring to the clinician that once it is satisfied, then
> there might be easier ways to document compliance and potentially
> reduce the risk of reprisal.
>
> DR. KATZ: Thank you. Dr. Jenkins?
>
> DR. JENKINS: Just one final point on this side I wanted to ask the
> committee to clarify because, as we went around the table I think it
> was very useful to hear your individual thoughts on the question, but
> I think I did hear some people responding to the question as it is
> written, which applies to the currently marketed modified-release
> opioids including OxyContin and some of the modified-release
> morphines. I heard some of the committee members seemingly talking
> towards Palladone. So, I guess I am interested in understanding
> whether the comments that we just heard apply to Palladone or to the
> currently approved modified-release opiates or all.
>
> DR. KATZ: Well, let\'s do that by show of hands. Whose comments were
> related? This is what I am going to ask so hold on for a second. Whose
> comments were related to just OxyContin, whose were related to just
> Palladone, and whose were related to both?
>
> OxyContin\--who was talking about OxyContin in their comments that
> they just made? OxyContin alone?
>
> \[Show of hands\]
>
> So, one person actually read the question. Who was talking about
> Palladone alone?
>
> \[Show of hands\]
>
> That is great. Who was talking about both medications without making a
> distinction?
>
> \[Show of hands\]
>
> Does that answer your question, Dr. Jenkins?
>
> DR. JENKINS: That is helpful. Thank you.
>
> DR. KATZ: Great! Dr. Rappaport?
>
> DR. RAPPAPORT: Could I just ask Dr. Dworkin to clarify why you felt
> that previous use of IR should not be a requirement?
>
> DR. DWORKIN: I guess I don\'t have any data on this. My impression is
> that there are some patients, and here I am not referring to
> Palladone; here I was referring to OxyContin for that specific
> qualification\--I think that 10 mg is a low enough available dose
> formulation that there are certain circumstances\--of course I am not
> a physician\--where that would be a dose that one could initiate a
> patient on and there wouldn\'t be a need for having that patient to
> have either been on an IR form of oxycodone or to have failed an IR
> form of oxycodone for some reason. Of course, as the label suggests,
> it is a different story entirely with Palladone.
>
> DR. KATZ: Any comments from our friends from Purdue prior to leaving
> this subject?
>
> DR. HADDOX: I appreciate Dr. Jenkins clarifying what my reading of
> question two is, and that is that recommended changes may further
> enhance the safe and effective use of the products, and I presume that
> means modified-release opioids which includes more than OxyContin and
> Palladone. There are a number of modified-release morphines, as has
> been mentioned, and there are also modified-release fentanyl products
> on the market.
>
> So, given that, I think that any restrictions you are talking about,
> if you are going to answer the question as I understand it, apply to
> all, to this class, if you will, or the subclass. I think that the
> screening recommendations that have been put forth, if I were in
> practice now doing this, would apply to that subclass, the
> modified-release opioids.
>
> I also think that we are leading ourselves a bit astray by breaking
> the indication that the FDA placed here for you as a sample into its
> tripartite units. This, unlike Palladone, is a three-tailed test. That
> is, it is not just moderate or severe pain. That is not the indication
> for OxyContin. If that is all you have, that is not the indication for
> OxyContin. If you have moderate to severe pain when a continuous,
> around-the-clock analgesic is needed for an extended period of
> time\--three conditions\--then you are a candidate for OxyContin. I
> think it is very, very different.
>
> I mean, I used to be a dentist, recall, and I had lots of people with
> moderate pain after dental extraction who did not meet the OxyContin
> indication because it wasn\'t going to last for an extended period of
> time; it was going to last for a couple of days. They would be on a
> nonsteroidal and they would be on Tylenol and it would be done. So, I
> think we need to keep that in mind.
>
> We have addressed this actually with DDMAC in an addendum which we are
> putting in our adds for OxyContin that says when used in this context,
> moderate or moderate to severe, it does not include commonplace and
> ordinary aches and pains, pulled muscles, cramps, sprains or similar
> discomforts. If the committee would think that would be useful to add
> to the PIs of all these things, we certainly would be willing to
> discuss that with the agency.
>
> I think it is also important to remember the slide that Dr. Lipman, I
> believe, showed yesterday of Dr. Cleland\'s work, showing that
> moderate pain has substantial impairment when it is persistent, not
> moderate pain from a sprained ankle that lasts for a day but moderate
> pain that is persistent.
>
> The issue about science, I think we need to get back to that. I have a
> concern about the discussion of placing \"not as a first-line drug\"
> in the package insert for OxyContin and I presume other non-Palladone
> modified-release drugs. The reason is there is a 20 mg dosage form for
> OxyContin. Remember the fourth test of Palladone is that you must
> require and be able to tolerate 12 mg a day of hydromorphone. That is
> why it can\'t be the first-line drug. It is not for use in people who
> are not opioid-tolerant. That is why it can\'t be the first-line drug.
>
> We have science the agency has seen where we have studied OxyContin in
> opioid-naive subjects and OxyContin was deemed safe and effective
> based on those data. Remember what Dr. Portenoy said yesterday, that
> there will be situations when in this continuum of care along a course
> of progressively more intense analgesics there might be a reason to
> start someone on an opioid as a first-line drug.
>
> From the issue of abuse, if someone was going to abuse a 10 mg
> OxyContin why would they pay \$10 for that on the street instead of
> buying two Percocets and getting the same amount of medicine? So, I
> think we have to be careful that we are not mixing apples and oranges
> here. Palladone is a different product for a different indication than
> OxyContin. There are overlaps. There are some similarities but they
> are not a one-on-one thing. I have data actually from two other
> studies on other things that we have discussed previously, if you so
> desire.
>
> DR. KATZ: I think that the critique is fair that it may not have been
> entirely clear as people were giving their answers whether they were
> talking to the entire class of modified-release opioids or just
> Palladone, OxyContin, etc. We certainly could revisit that in detail
> now but, given the time and given that we still have a long agenda, I
> would pose the question to the folks from the FDA as to whether you
> would like us to take the time to go through that clarification or
> whether you have heard what you need to hear from us.
>
> DR. JENKINS: I would suggest that we move on because there are a lot
> of additional issues that are beyond just the indication, and I think
> the points we have heard are very valid. No one, I think, around the
> table was thinking of this just as a moderate to severe pain
> indication. That was just to get to some of the suggestions that have
> been made. No one was taking this out of context and I don\'t think
> the committee members, as we went around the table, were taking it out
> of context because most of the committee members actually advised
> adding additional type of qualifications to the indication. So, I
> don\'t really think, from the agency perspective, it is necessary to
> revisit the issue. I would like to get on to the questions about risk
> management plans, access, etc.
>
> One thing to clarify, the way these questions were set up, the first
> three Roman numeral questions, and number III has a lot of sub-parts,
> were really focused on the currently approved modified-release
> opiates, with the final question being specifically applied to
> Palladone and whether you think that the Palladone risk management
> plan is adequate for safe and effective use. So, you may want to keep
> that in mind as you go through the questions under Roman numeral III.
> They are primarily directed towards the currently available products
> but, obviously, there is overlap with the Palladone and the Palladone
> plan is the one that you have heard most about today, and I won\'t be
> surprised if you have trouble distinguish and keeping those as true
> separate categories.
>
> DR. KATZ: Thank you. One last observation I will make before we take
> our break is that it seems clear that people who treat pain for a
> living and who worry about the problem of under-treatment of pain tend
> to favor the more open label, whereas people who treat the
> complications of opioid abuse, obviously, favor the more restrictive
> labeling. So, what is needed is for somebody sitting on top of both of
> our groups to kind of weigh and balance all of it and put it together
> in the interest of public health. I am not sure any one individual of
> us has the capability of doing that sitting around the table. A
> 15-minute break.
>
> \[Brief recess\]
>
> DR. KATZ: Let\'s move on. I know this is the time when people\'s
> stamina starts to drag and people start to think about how they are
> getting home, but let\'s try to redouble our mental energies towards
> the last hour and a half of our meeting. I am going to read the next
> question, which will take me half a minute or so, and then we can
> start discussion.
>
> The FDA is currently reviewing a number of proposed risk management
> plans for modified-release opiate analgesics. Again to reiterate what
> Dr. Jenkins said earlier, this question will be referring to currently
> available modified-release opiate analgesics. Is that right, Dr.
> Jenkins?
>
> DR. JENKINS: Obviously, we are also reviewing the Palladone plan but
> we are asking you a specific question later about Palladone.
>
> DR. KATZ: So, we should consider that this question is with relation
> to all modified-release opioid analgesics?
>
> DR. JENKINS: Yes, this is kind of more of a generic question.
>
> DR. KATZ: Fair enough. Thank you for the clarification.
>
> In order to make informed and appropriate determinations in regard to
> these risk management plans, we need to carefully consider which
> elements of risk management would most likely increase the safe use of
> these products for legitimate patients and result in a reduction in
> abuse, overdose, addiction, and misuse in the medical setting. In
> addition, we must also take into consideration the potential adverse
> impact of these various risk management elements on patients,
> prescribers, and pharmacists, as we do not wish to impede proper pain
> management. In light of these concerns, please discuss the following
> elements of risk management.
>
> Now we are going to discuss number one. That will be the topic of
> discussion for the next little while: Restricted access\--some risk
> management programs have attempted to manage risk of drugs through
> various interventions that attempt to limit product use to appropriate
> patients. Examples of such interventions have included efforts to
> limit prescribing to a subgroup of physicians based on established
> expertise or completion of specific training in safe use of the drug
> or to limit prescribing to a subgroup of patients such as patients who
> have failed other available therapies or patients who have the most
> severe manifestations of the disease.
>
> Discuss the role of restrictions in access in addressing concerns
> about the abuse and misuse of modified-release opioid products and how
> any such measures may impact on the use of these products in
> appropriate patients.
>
> So, let me just focus everybody\'s attention on the key elements of
> this very long question. Restricting to certain types of physicians,
> would that help solve the problems we are concerned about? Would that
> impede appropriate pain management? Restricting to certain kinds of
> patients, would that help solve the problems we are concerned about?
> Would that have any negative impact on appropriate pain management?
> Open for discussion. Dr. Shafer?
>
> DR. SHAFER: First of all, I need some clarification. When we are
> talking about restriction here, are we talking about restriction
> through the process of, for example, the package insert where it says
> only these physicians should write prescriptions, or are we talking
> about some sort of administrative mechanism that actually assures that
> either the patients have met certain qualifications, for example, the
> pharmacists have to verify the presence of certain lab data for them
> to even get physical access to the drug?
>
> DR. KATZ: My understanding is that this could refer to any sort of
> administrative mechanism for restricting access to physicians or
> patients. Dr. Jenkins?
>
> DR. JENKINS: Yes, this is primarily intended towards things that go
> beyond just the package insert. As Dr. Trontell described in her
> presentation yesterday, there are examples of risk management programs
> that have gone beyond the package insert and actually put in place
> mechanisms such as those that are described here. So, we are talking
> here about restrictions to access that go beyond simply the indication
> statement or any statements in the labeling about who should or should
> not receive the drug or who should or should not be prescribing the
> drug. We are talking here more about any specific programs to try to
> make sure those limitations actually occur.
>
> DR. KATZ: So, that is another level of the question I guess, if you
> believe that this is an appropriate goal of restricting to certain
> patients or physicians, what sorts of programs could one envision to
> implement such restrictions? Go ahead.
>
> DR. SHAFER: Then just to ask for more clarification, in terms of these
> programs, are we talking about all Class II, or are we talking about
> Class II modified and extended release, or are we talking about
> Palladone?
>
> DR. KATZ: Go ahead.
>
> DR. JENKINS: We are talking about the Class II modified-release
> products.
>
> DR. KATZ: Dr. Aronson, you were next.
>
> DR. ARONSON: Yes, I will speak to the question. My opinion is that
> access to a certain specific physician group ought to be liberal as we
> need to recognize that the majority of physicians in our country are
> not specialists and there are an awful lot of patients out there with
> pain that would likely be seeing those physicians who are not
> specialists on a first-line basis.
>
> Having said that, I think that it is reasonable that we expect a
> certain hurdle\--I think that was the word that was coined
> earlier\--but a certain set of criteria that anybody meets to
> demonstrate their understanding of the implications of writing these
> particular drugs. I think we ought to be careful to establish those
> criteria so that they are openly accessible to all physicians but
> significantly high enough that there is some degree of assurance that
> they do understand the implications of writing these drugs.
>
> DR. KATZ: Just to be clear, you would not suggest restricting by
> specialty but you would suggest restricting to physicians who have in
> some way, shape or form demonstrated competence to prescribe these
> particular products.
>
> DR. ARONSON: Correct.
>
> DR. KATZ: Dr. Strom, you were next.
>
> DR. STROM: By nature I am an activist and believe more in restriction
> than education because we know education doesn\'t work, at least
> beyond medical school. But in this case I think restriction would be a
> mistake. The reason is that I think any intervention has side effects,
> as was talked about a few times, and it is very clear that if you
> restricted access here it would reduce access to the drug to patients
> who need it for pain. It is not at all clear that it would in any way
> affect the problem of drug abuse or overuse. If in fact there was less
> of the modified-release opioids so people would use less of that, they
> would use more of something else. So, absent evidence or even reason
> to think that it would really affect the nation\'s problem, reduce the
> nation\'s problem of opiate abuse, I would think that restricting
> access would cause problems and would not have any benefit.
>
> DR. KATZ: So, you are saying that you also would not restrict, but you
> also don\'t even like the idea of restricting by competence because
> you are not persuaded that one could actually create competence
> through the typical educational programs that we implement. Dr.
> Maxwell, you are next.
>
> DR. MAXWELL: I want to talk just about Palladone for a minute because
> something was in the presentation yesterday that was not discussed
> that I think we need to think about. When Xyrem was brought to
> market\--now, Xyrem is gamma hydroxobuterate and to avoid the abuse
> problems it is available only through a central pharmacy. So, it would
> seem to me that as this drug rolls out\--and I think those of us in
> addictionology almost think it is not going to be a problem of people
> turning into addicts, it is going to be a problem of an awful lot of
> drug deaths on the streets. It is going to be in bodies; it is not
> going to be an addiction because of the strength of this drug and the
> potential for abuse and the side effects.
>
> Could it not come through a central pharmacy? That way you can assure
> the doctor that for him even to write it there would be controls on
> the distribution so we could get out of this business of the back door
> sort of thing. If the drug turns out to be less abused and not the
> problem we thought, it could spread out. But I am very worried about
> dead people. We may ease the pain of some but we are going to kill an
> awful lot of others with this drug.
>
> DR. KATZ: So, you would favor restricted distribution through certain
> pharmacies, as well as restricting to certain types of physicians.
>
> DR. MAXWELL: No, I didn\'t say that about restricting physicians. Is
> there some sort of course I can take, an educational course?
>
> DR. STROM: Can I just clarify, are we talking about Palladone now?
>
> DR. MAXWELL: Yes, Palladone.
>
> DR. STROM: I wasn\'t talking about Palladone, I was talking about
> other non-Palladone drugs.
>
> DR. KATZ: That is a fair clarification. We should actually stick with
> non-Palladone\--
>
> DR. MAXWELL: But that is an option that needed to come out that was
> not discussed yesterday that should have been.
>
> DR. KATZ: Fair enough. Dr. Bril?
>
> DR. BRIL: I guess my experience is a little bit different. I have a
> couple of thoughts about how you might find this out, your
> effectiveness and get some evidence here. I don\'t know how long you
> have had to have a DEA license to prescribe Class II drugs in the U.S.
> That contrasts I think to our situation where we don\'t need a license
> from, say, our CMP to prescribe Class II drugs or the equivalent. So,
> if you knew the interval before and you looked at the level of
> addiction in the country before the licenses became mandatory and then
> compared to an interval afterwards you might see if you have actually
> influenced the percentage of addicts that you have through restricting
> or granting special licenses through the DEA to physicians. That may
> be one way to look at this question.
>
> The other way, you could actually perhaps compare a population base
> here with one north of the border to look at the percentage of opiate
> addiction, if you can get comparable numbers from a place, you know,
> where you have restrictions to a place where you don\'t have the same
> kind of restrictions to see whether restrictions work.
>
> Those are just two approaches. I don\'t have that information myself.
> I don\'t know of any of this information in Canada; maybe Health
> Canada does.
>
> MS. NAGEL: We register any physician that applies that has a
> legitimate license for the state. There is no delay. When they come in
> and pay our license, then they are able to show that by the state. We
> provide them with a registration. There is no lag. There are no
> qualifications other than a state license.
>
> DR. KATZ: Just to reiterate that, you don\'t need to have any
> qualifications, other than an M.D. degree in this country. You don\'t
> need to demonstrate competence in prescribing controlled substances in
> the United States of America in order to obtain a DEA registration to
> do just that. Is that correct?
>
> MS. NAGEL: Yes.
>
> DR. KATZ: Dr. Shafer, you were up next.
>
> DR. SHAFER: First of all, let me say I would strongly support, by way
> of restriction, that the DEA require people to have a certain amount
> of CME credits before getting CII approval across the category. I
> don\'t believe about education not working. Actually education is
> quite effective, having recently taken a driver training course to
> that effect.
>
> If people have to take a certain number of CMEs and, you know, it can
> be Internet based and there are all sorts of interesting ways of doing
> this for the whole Class II opioids, I think that is a smart thing to
> do. I am uncomfortable differentiating the intermediate release and
> the slow release from the immediate-release products because I think
> that in doing so you may kind of trivialize the risk of the other
> ones. These are all dangerous drugs, and I am not convinced from the
> data that I have seen that any particular opioid in the Class II
> category is intrinsically more dangerous than any other one, or that
> any release pattern is intrinsically more dangerous. I think they are
> all dangerous.
>
> Now, there are some unique properties. If somebody were to distill the
> hydromorphone out of the Palladone tablets, they would have something
> that would look like heroin. So, that is an interesting risk that is a
> little bit unique to this drug because of the characteristics of the
> IV formulation that might be distilled out. That is the kind of thing
> physicians need to be educated about through a program. Otherwise, I
> would not favor a program that targeted either slow release or that
> targeted a particular molecule in the Class II drugs.
>
> DR. KATZ: Laura Nagel, s response to the education of physicians
> issue?
>
> MS. NAGEL: For everybody\'s information, we have been working with FDA
> and this is one of the things we have been cooperatively working on
> with FDA. Dr. Katz actually brought it up six months ago about trying
> to work with the state medical boards to require some sort of
> continuing education before you would be able to renew your DEA
> registration.
>
> What we will have to do, just for your information because nothing in
> the government moves quickly, we will have to actually have
> legislation. The way the law is written it says we \"shall\" issue a
> registration. So, if we are going to put a requirement on your
> registration that you would, in fact, have gotten some up to date
> education, we take a very positive view about it. We do believe there
> are the outdated and the duped, and we think this is probably the best
> way for us to try and reach them. So, that is something that we are
> working with the FDA on.
>
> I am hopeful that actually Massachusetts could be somewhere\--we could
> kind of go first. But we are going to have to work with the state
> medical boards because I don\'t think you want DEA defining practice
> of medicine. So, we are going to have to go back through your state
> boards and work with them but that is something that we absolutely do
> agree with you on, and I can speak for the FDA Commissioner, he does
> also.
>
> DR. KATZ: Thank you very much. The second piece of your comment was
> related to whether we are making a false distinction between modified
> release and immediate release.
>
> DR. SHAFER: The number one drug on all of these lists has been
> Vicodin. So, if you want to talk about the biggest single problem that
> we face as a health problem here, in the United States, in the way of
> diversion of prescription drugs, it is Vicodin, which is an
> immediate-release drug.
>
> DR. KATZ: This may be an artifact of the purpose of this meeting and I
> don\'t know if, Dr. Rappaport and Dr. Jenkins, you want to address
> that issue.
>
> DR. JENKINS: We clearly recognize that all the opiates are abused and
> the comment about the hydrocodone\--I guess Vicodin\--being the one
> that always shows up at the top of the list. We were focusing here on
> the sustained-release products or the modified-release products
> because of their unique characteristic of having such a high dose in a
> given tablet and the risk of serious adverse events and death, as well
> as potentially the risk of greater liability for addiction because of
> that characteristic of the product, very high dose, sustained-release
> characteristics that can be overcome by someone who has that desire.
> So, that is why we were really focusing here\--we recognize that all
> of these products are abused and will be working with DEA on all these
> products, but for now we were focusing on the modified-release
> products.
>
> DR. KATZ: Dr. Rose, you were next.
>
> DR. ROSE: In talking about whether or not we should be restricting the
> prescription of these drugs, I would be in favor of restricting the
> modified-release drugs in some way, keeping in mind that we already
> have the OxyContin out on the market which does have a history now of
> abuse, both being diverted by the patient who receives the
> prescription from a duped physician to physicians who are running drug
> mills.
>
> So, there is definitely a need for education like Dr. Aronson said.
> There has also been the comment made about education doesn\'t work.
> So, I would like to combine those and say we should restrict them to
> the educated physician, restrict the prescription of that to the
> educated physician but we would have to do a little bit of stepping
> back because I am talking about all of the modified-release drugs and
> that would include OxyContin. And, now we have physicians who can all
> prescribe the drug. So, it would be kind of hard to get that into the
> practice of medicine.
>
> In a way then, I am just talking about Palladone. I think it is
> appropriate to have some restrictions on the prescription or these
> drugs, at least at the beginning. We are here basically to talk about
> Palladone, and if we have made mistakes in the past as it relates to
> OxyContin, it doesn\'t mean that we have to make more mistakes in the
> future about Palladone. I am not saying keep Palladone off the market;
> what I am saying is that if it is going to be marketed, market it in
> an educating fashion. So, I would be in favor of a strong education
> aspect in this.
>
> Then, the aspect of how long some physician has been in practice
> before they could prescribe any one of these drugs, my impression from
> just hearing stories in Pennsylvania is that some of the doctors, who
> are running drug mills and prescribing these in a criminal fashion, is
> that some of them have been in practice for years, and years, and
> years, and they are tired of practicing medicine and they are running
> these mills, and they are making a lot of money on their way to
> retirement. So, I don\'t think that the number of years you have been
> in practice is really the answer to that.
>
> DR. KATZ: Dr. Cush?
>
> DR. CUSH: I am generally opposed to restriction but I do think that
> somewhere, not only in the package insert which is usually not read by
> physicians\--I know that the agency would like to think that they
> actually do read package inserts but I think studies have shown well
> that doctors don\'t. They go to them as references for particular
> issues rather than to read the whole thing to be instructed on the
> proper use of a medicine. I think we have to indicate somewhere along
> the way the gravity of writing a Schedule II drug, including this new
> drug Palladone.
>
> So, either you do some sort of extra course work and then you become
> part of the club that can write this prescription, or I will make a
> case for a one-page registration that can be done on a periodic basis
> where patients can receive that. In that one-page form that is filled
> out they could have documentation of need, of goals, of outcomes that
> would include risk assessments and outcomes that could also include
> serious adverse events and that would be, again, instructive as far as
> the overall outcomes of this program, and what it means, and I think
> we could learn a lot from that and that would be very important as far
> as whether this should be applied to other drugs in the same class.
>
> I do think that such a measure does not restrict people from getting
> this particular new drug because there are plenty of other drugs
> available and this new drug does not provide any tremendous unmet need
> so that we need to make it open to as many people as possible. I think
> it is a good opportunity that we should study this drug as it enters
> the market.
>
> DR. KATZ: It is probably my fault that you are talking about both
> Palladone and the other modified-release opioids together. So, let me
> ask you to clarify your suggestion about a patient registry then. It
> sounded like you were suggesting that patients should be entered into
> a patient registry. Are you talking about patients who are prescribed
> any modified-release opioid, or just patients who are prescribed
> Palladone when it comes on the market, or something else?
>
> DR. CUSH: I think you have to start somewhere and I think you should
> start with a new drug on the market. If that proves successful as a
> deterrent, as a means of fixing the problem of diversion, of fixing
> abuse or lowering abuse potential, then it should be adopted to the
> class. But I think that you have to start somewhere and, again, I
> think that one page is not an impediment in my practice of medicine. I
> do this all the time. The patient is leaving the room\--oh, I need to
> fill out a prescription for you to go to physical therapy, which is a
> one page thing. I have to write out a form. I do this all the time and
> it usually reflects the context of what happened in the course of the
> visit, which in this case would go to the issues of risk assessment
> and reasonable goals and why I am using this particular drug.
>
> DR. KATZ: I haven\'t heard anybody say that they favor restricting the
> use of modified-release opioids a priori to a certain type of patient,
> one with this disease, that disease, you know, this history, that
> history. Am I missing something? Is anybody actually in favor of
> restricting to a certain kind of patient and I missed that? So, that
> is a take-home message then.
>
> The suggestion is on the table about patient registry, but I just want
> to also follow-up on the suggestion that came up earlier about
> restricting to physicians that meet some competency criteria. The
> reason I want to talk about that for a second is that it seems like
> that would be very unlikely to impede the appropriate practice of
> medicine in terms of the negative potential of various interventions
> that we could come up with. Whether it would have a positive effect on
> reducing diversion, addiction etc. is another question, but is there
> anybody who feels that there would be big downsides to establishing
> physician competency in order to prescribe these drugs? Bob Dworkin,
> did you have anything you wanted to say at this point of time? You are
> actually next on the list.
>
> DR. DWORKIN: I was going to make the same suggestion that Steve was
> going to make about DEA requiring some minimal level of CME. My
> concern, to follow-up on your question, is that it sounded like this
> could be a five- to ten-year process, and then what are we going to do
> while the DEA sets into place a CME requirement for re-registration?
> If it really is going to take five- to ten-years, it is nice to know
> that that is on the long horizon but what about the near horizon?
>
> MS. NAGEL: And that is actually correct, sir. It would not be a quick
> fix; it would be a long-term project. Thank you for bringing that up
> because I don\'t want to leave anybody with the impression that we are
> going to do this quickly. It is something that we hope to do but it
> will be long-term, not a short-term.
>
> DR. DWORKIN: So, it seems like we are all in favor of that but that
> doesn\'t really address any of the need for the next ten years.
>
> DR. KATZ: Although it may be possible, in collaboration with the state
> medical boards, to fast track this pre-legislation. Is that correct?
>
> MS. NAGEL: That is what we hope to do. We hope to get a couple of
> states together and they may have data to present in the future on the
> utility of the program. I mean, we hope to do what we can quickly but
> the reality is\--I don\'t want to say ten but I would say to you it is
> probably a three- to a five-year process because legislation will have
> to get changed; medical boards will have to get on. So, the short-term
> is the products that are out now and more products that are coming out
> soon.
>
> DR. KATZ: Dr. Trontell, do you have something to add?
>
> DR. TRONTELL: Not on the topic of physician competency but I will have
> a question of clarification about patient registration based on Dr.
> Cush\'s remarks. I can wait if you like.
>
> DR. KATZ: Go ahead and do it now.
>
> DR. TRONTELL: If you could clarify, since we have tended in the agency
> to refer to registries as, in fact, some central repository of
> information on patients, are you referring to something that might be
> maintained, say, in the patient\'s chart with the physician in the
> nature of a physician-patient agreement, or something, in fact, where
> there is some collection of these data and oversight?
>
> DR. CUSH: I would envision this being not part of the chart because it
> is something that goes along with the prescription, and it should
> actually reflect what should be in the note or the context of what
> happened in the course of the visit. So, if it were to be copied and
> put in there, that would be fine but it should also reflect what is in
> there anyway. But I would envision this thing either being given with
> the prescription to the patient and the patient takes both to the
> pharmacy and then it gets submitted and sent to a central depository.
> Then you can use that to collect information on a patient on a drug
> over time. Again, it has to show up with every prescription. I mean, I
> have heard that sometimes you can only give two weeks at a time, so
> maybe quarterly patients are registered or a patient is registered if
> a doctor goes on line and fills this stuff out on line by doing some
> check boxes and it is checked that way.
>
> DR. KATZ: Thank you. Based on time, we only have time to spend another
> minute or two to talk about restricted distribution by either patients
> or physicians. So I want to try to restrict the next few comments to
> comments specifically to the area of restricted distribution, and, Dr.
> Gillett, you are next.
>
> DR. GILLETT: As a big supporter of extension work, we use that for
> pesticides because restricted use pesticides have to be sold by a
> person with a license that gets four units each year of continuing
> education. This means that the hardware store salesman or the
> pesticide applicator has to have that license. You at least ought to
> have that same level of teaching education for a drug of this class.
>
> DR. KATZ: So, you are in favor or requiring demonstration of physician
> competency\--
>
> DR. GILLETT: yes.
>
> DR. KATZ: \--for prescribing all modified-release opioids.
>
> DR. GILLETT: Yes.
>
> DR. KATZ: Dr. Skipper, you are next.
>
> DR. SKIPPER: I wanted to mention that it appeared from the data, from
> the DAWN data and other data that the interpretation of OxyContin did
> recruit new non-medical substance abusers, and it is my impression
> that there was a significant death rate, you know, 500 to 1,000 people
> a year, from overdoses of OxyContin. That has been my impression. I
> don\'t know, we didn\'t hear any discussion of the death rate.
>
> Anyway, I have been wanting to mention something during this entire
> meeting, and that is that I think there is a significant stigma
> against substance abusers. If we were talking about a new antibiotic
> coming on the market that was taken by kids and they died, then it
> probably wouldn\'t get introduced. So, somehow we are feeling okay
> about introducing more drugs that are probably going to be abused and
> kill people, and it is probably going to be kids that are
> experimenting and I just think we need to keep that in mind.
>
> DR. KATZ: Dr. Crawford, last comment on this issue.
>
> DR. CRAWFORD: Thank you. It is a quick one. I am just a bit sensitive
> that all of our discussion has focused on the diagnosis prescribing
> side to physicians. There are others with prescriptive authority.
> Whatever occurs with physicians should also be extended to such as
> advanced practice nurse practitioners and perhaps dentists with
> certain indications, and others. So, that is my only comment.
>
> DR. KATZ: That is a very good point. We should all be probably using
> healthcare providers or some more general term like that for the
> purpose of this discussion. Is that what you are saying?
>
> DR. CRAWFORD: Actually, I would like to see in any of the language
> physicians and other prescribers.
>
> DR. KATZ: Thank you. Referring to my colleagues from the FDA for a
> second, would it be useful to go around the table and see what
> people\'s sort of final stances are on restricted distribution through
> either pharmacy, competency demonstration, patient types, whatever the
> individual would like to put forth, or are you satisfied with what you
> have heard?
>
> DR. JENKINS: I think we have heard a pretty strong sense from the
> members of the committee that they favor educational competency, some
> sort of maybe working with state medical boards and/or the DEA to have
> a requirement to renew your authority to prescribe. I haven\'t heard
> anyone suggesting that we should limit in any way the ability to
> prescribe these drugs to, say, pain specialists, anesthesiologists, in
> other words, not general internists or family practitioners. So, if
> anyone feels that we should be restricting the specialty of the
> physician to prescribe, it would be interesting to hear their thought
> process there.
>
> I did hear some suggestion that maybe some of that might apply to
> Palladone because of some of its unique characteristics, and I did
> hear one suggestion about maybe a central pharmacy as a way to
> introduce a drug like Palladone.
>
> DR. KATZ: So, holding off on Palladone for a moment, is there anything
> else you feel you need to hear about question three as we have
> discussed restricted access to existing or forthcoming opioids?
>
> DR. RAPPAPORT: Well, by training is still an issue that should apply
> to all of the products. So, as Dr. Jenkins just asked, maybe we should
> make sure that there is nobody who feels that we should put any
> restrictions by training for the general class physician, prescriber
> training.
>
> DR. KATZ: I am sorry, could you just articulate that question one more
> time, Bob?
>
> DR. RAPPAPORT: Restricting by specialty or physician training is still
> something that could apply to all of the extended-release opioids, and
> if there is anybody who maybe feels we should do that, we haven\'t
> really addressed that specifically.
>
> DR. KATZ: My sense is that everyone who was endorsing education as a
> requirement for dispensing modified-release opioids was referring to
> the whole class and I think maybe as a requirement of DEA
> registration, referring to all opioids.
>
> DR. RAPPAPORT: Yes, I understand that, but I am also asking beyond
> that, is there anybody who feels there should be limitations by
> specialty training.
>
> DR. KATZ: Does anybody feel that there should be limitations by
> specialty training? Again, we will talk about Palladone in a moment.
>
> DR. JENKINS: I think a corollary to that question, as Dr. Trontell
> described yesterday, is that some of the risk management programs have
> actually had, for example, physician attestations that they are aware
> of the appropriate use of the drug and they maybe have taken a course
> offered by the sponsor. Is anyone suggesting that we should be
> considering such a program, beyond what we talked about, where you
> would have to have some educational requirement to get your DEA
> license? Is anyone suggesting that we should have something where, in
> order to prescribe OxyContin, in order to prescribe modified-release
> opioids, or Palladone that you should have to, you know, say I have
> taken this course? I am aware of the indication. I am aware of the
> safe use\--basically a physician attestation of adequate training?
>
> DR. KATZ: Dr. Ciraulo?
>
> DR. CIRAULO: I would recommend you follow the buprenorphine model and
> be certified in a similar way.
>
> DR. KATZ: Dr. Rose?
>
> DR. ROSE: It has been suggested that there be some kind of a registry.
> I believe Dr. Cush made that recommendation. I would be opposed to the
> registry because there are privacy issues here. A lot of patients
> would not want their information to be going to the pharmacist, to be
> seen by the pharmacist. But I am very much in favor of requiring the
> physician to make certain documentation on their own medical chart so
> that if it were necessary to see that chart by any regulators or any
> DEA agents coming into the office, they could see that there was
> documentation on that patient\'s chart for prescribing.
>
> DR. KATZ: It sounds like we are ready to move on to the next issue. I
> am going to skip over to the final page of our list of questions where
> it says \"question for day 2.\" Since there are only 15 minutes left
> in our meeting and since we are supposed to talk about the Palladone
> risk management program, it seems like we ought to get to that. Then
> if we have time we can cycle back to some of the other details of the
> other program suggestions.
>
> So, I will go ahead and read this question: Based on the information
> that has been presented at this meeting, and taking into account your
> earlier discussion and deliberation about risk management plans for
> modified-release opioids, does the Palladone risk management plan,
> including its proposed labeling and indications, define a program that
> will likely result in safe use of the product and limit the potential
> for abuse and misuse of the product while assuring that appropriate
> patients are able to receive the medication?
>
> Open discussion. I am starting my list all over again so if you would
> like to be recognized, raise your hand. Dr. Aronson then Dr. Cush.
>
> DR. ARONSON: One of the things that I heard this morning in the
> multifaceted plan by industry to roll out this product was a proposal
> to do it in a staggered, if you will, staged launch. It was mentioned
> that there was a proposed four-month lag to separate their first
> initial selective launch before they implement their second. I
> question the legitimacy, for lack of a better word, of that time line.
> We did not, for example, see data yet analyzed from 2002 with respect
> to the DAWN and other, if you will, outcomes from their RADARS program
> and if it is already ten months into year before we have had a chance
> to analyze 2002, why would they think four months of a staged launch
> should serve any positive purpose in their wishing to have feedback?
> So, I would propose that that be extended considerably before they go
> on to their next phase.
>
> DR. KATZ: Let me dwell on what you are saying for a second. It sounds
> like your first point is that you are endorsing a staged launch.
> Right? It seems like you are implicitly endorsing it.
>
> DR. ARONSON: I accept the concept of rolling this drug out in a
> staged, selective manner, yes.
>
> DR. KATZ: Your second point is that while you endorse and like the
> idea of a staged launch, you feel like four months is too short for
> the data collection and reporting and all the other reasons that you
> alluded to.
>
> DR. ARONSON: I don\'t think we would be able to gain anything one way
> or the other by that time line.
>
> DR. KATZ: Right. Do you have a sense for what time period you would
> recommend?
>
> DR. ARONSON: Based on history, I would say a year. We are now at least
> ten months into this year and we have not yet analyzed the data that
> they wished to have presented to us today from 2002.
>
> DR. KATZ: Fine. The third piece of your comment that I would like to
> focus on is that it sounds like you have some idea of what data one
> would need to see in order to determine whether that first stage in
> the staged launch should be followed by a second stage.
>
> DR. ARONSON: Well, I spoke to that earlier as well. I wanted to know
> what metric, what tools they were actually going to analyze in a
> processed outcome manner to decide whether or not they would go on to
> their next level, and I did not hear that answer very clearly. I think
> we do need to have that answer. I think any strategy has to have a
> goal, an endpoint, and I would like to know at least prospectively
> what that is before we accept their plan.
>
> DR. KATZ: Well, i would feel back to put the sponsor on the spot
> again; I have done that to them a couple of times; so I will put you
> on the spot instead. What information would you like to see?
> Forgetting about this database or that database, as a clinician or
> someone interested in these medications, what information do you think
> would be necessary in order to decide whether the results of that
> first stage suggested you should go to stage two?
>
> DR. ARONSON: It is my presumption that the whole initiation of the
> RADARS type program, etc. was to understand better for the purposes of
> minimizing the risk of diversion and abusive behaviors with what is
> potentially a very dangerous drug. So, I would like to know, in fact,
> that we do have data that help us understand that, and whatever
> behavior modification we would propose to implement does have an
> effect to mitigate that and prevent it.
>
> DR. KATZ: Thanks. Dr. Cush is next.
>
> DR. CUSH: I think that the manufacture of the RADARS program was
> multifaceted and impressive and I applaud them for that. I think it is
> an important arm of a risk management program, but I think as far as
> the question is stated, will it actually result in the safe use of the
> product and limit the potential for abuse, I think the program they
> laid out is one that collects data and points out problems and tells
> us where diversion may be occurring or problems are occurring, but we
> have kind of already heard that with the drugs that have already been
> out, like OxyContin and what-not. I think it is going to give us new
> information on a new product and maybe how that is being abused. Maybe
> that will generate answers, but I don\'t think that this necessarily,
> as it is laid out, is a program that will actually encourage safe use
> and discourage the abuse. I think that we need other measures to do
> that.
>
> DR. KATZ: So, the program consisted of data collection and then also
> analysis, and there were never interventions that the sponsor proposed
> in response to signals that they might receive from their data. Are
> you suggesting that you don\'t feel that the interventions that they
> proposed would be effective in reducing problems that might arise?
>
> DR. CUSH: I don\'t recall any specific interventions, other than
> calling the DEA where appropriate, that were going to be identifiably
> impressive, at least I don\'t recall any from their presentation. I
> think, again, EAB will be helpful in analyzing that data. It is an
> impressive group of people and I am sure they will do a good job and
> come up with things but, as set forth, the program itself does not
> meet the stated goals of the question for day two.
>
> DR. KATZ: It sounds like we are wrestling with the issue of whether
> the data that is going to be collected will be sufficiently
> informative to address the issues at hand and, secondly, whether the
> interventions that are proposed will address the problems revealed by
> that data.
>
> I am actually going to turn to Dave Haddox for a minute. Specifically,
> Dave, if you could remind us what the interventions are?
>
> DR. HADDOX: The risk management program for Palladone is not just the
> RADARS system. The RADARS is one component of the surveillance aspect
> of the risk management program. The interventions include everything
> from the educational sorts of things we talked about, the outreach,
> making sure that practitioners have proper patient selection, the
> patient package insert, those sorts of things; and targeted
> interventions based on findings from RADARS or from other sources,
> other signals; and the nature of the intervention will depend upon the
> nature of the signal.
>
> I would also like to clarify the phased launch. I think maybe I
> wasn\'t clear this morning. The phased launch, the four months, what
> we are going to be testing during the four months\--we will, of
> course, be collecting RADARS data simultaneously but the goal of that
> is specifically to address the concern that Mr. Woodworth from the DEA
> mentioned yesterday, and that was message integrity. Does the
> practitioner understand the message\--proper patient selection, proper
> dosing, how to minimize risk and abuse, those sorts of things? That is
> what we are going to be testing. We will certainly be looking at this
> concurrently, but at four months we think is probably a reasonable
> break point to see what we have found, if 95 percent of the physicians
> got the message or have 5 percent gotten the message right.
>
> DR. KATZ: Thank you. Dr. Aronson, would robust data on the integrity
> of the messages that are heard by the various individuals in the
> cycle\--would message integrity be sufficient for you to go on to the
> second stage of launch?
>
> DR. ARONSON: Not necessarily. How are you going to determine whether
> or not they got the message?
>
> DR. HADDOX: The plan is to do research to find out whether they got
> it. You can do telephones; you can do surveys; you can do face-to-face
> interviews and basically you sit down, very much like the IMS product
> to which Mr. Woodworth made reference yesterday, and say what do you
> know about Palladone? What did you get? Find out what the practitioner
> understands, the person who is dispensing, the person who is
> prescribing. If they say, well, gee, it is for moderate to severe pain
> where a round-the-clock opioid is necessary for a certain period of
> time in an opioid-tolerant patient, good, you got that, you got the
> proper patient selection. What do you know about the dosing? Is it the
> first opioid or not? Those sorts of messages.
>
> DR. KATZ: Let me interrupt for just a minute. We are not going to get
> into the details now about exactly how those data are going to be
> collected so for the purpose of discussion, assuming that those data
> could be collected and reported in four months and you can feel
> confident about message integrity, that everybody is hearing the right
> message about this product, is that sufficient for you to proceed to
> the next stage of the launch?
>
> DR. ARONSON: The concern I have, and I think it has been echoed by
> many during the sessions over the last few days, is not that this is a
> good drug when used properly and intended for the right subset of
> patients, but the consequence of it being misuse is real and alarming
> to all of us. So, what I would hope to get out of this staged, if you
> will, launch is an understanding of the potential harm. However not
> intended, it is nevertheless real. There is that potential and so how
> can we learn about modifying its further, if you will, launch to
> minimize that?
>
> DR. KATZ: You are saying that no is the answer to my question? That
> hearing about the message integrity would not be sufficient for you to
> go to the next stage?
>
> DR. ARONSON: Not with that time line.
>
> DR. KATZ: Dr. Trontell, did you have a comment to add?
>
> DR. TRONTELL: Yes, a question for Dr. Haddox, to this point have you
> done, in fact, any pretesting of message integrity, and might you
> explain why you would test the message after the product was on the
> market as opposed to before?
>
> DR. HADDOX: I am not aware that we have done any. That that is called
> preapproval promotion, isn\'t it? I think that is proscribed.
>
> DR. TRONTELL: Certainly, in the case of patient information, label
> comprehension and other forms of assessment of whether or not the
> informational content has been understood.
>
> DR. HADDOX: Actually, the phased launch is going to be talking about
> the message integrity of prescribers and dispensers. That is the focus
> right now, not talking about consumers or caregivers, not that we
> wouldn\'t consider that as well but that wasn\'t the focus.
>
> DR. TRONTELL: And my suggestion was if education and comprehension of
> the information were felt to be critical, I might suggest, or ask in
> this instance whether or not you thought to extend that to physicians
> as well since they are tested and certified in other settings.
>
> DR. KATZ: Dr. Jenkins?
>
> DR. JENKINS: I think the question maybe you are trying to get at about
> the message integrity is, is it enough to know that they got the
> message? How are we going to test for actual behavior? I think it is
> very common to note that people know what the message is. We all know
> what the speed limit is on I-270 but we also know how many people
> adhere to that speed limit and how they rationalize why it doesn\'t
> apply to them. So, I guess I am interested in knowing how is Purdue
> Pharma planning, during this phased launch, to not only assess message
> integrity but actual behavior of implementing that message.
>
> DR. HADDOX: Well, as I mentioned in my presentation, this is an
> evolution right now. We have been thinking about this for a while. One
> of the things we will be doing, of course, is looking in the databases
> where one can track a unique patient, which are not very common. We
> could assess that this was a person who had been exposed to another
> opioid and, if they had never been on an opioid before and were all of
> a sudden exposed to Palladone, that would be a clue that the behavior
> was not correct because it would then be a first-line opioid. But we
> are open to suggestions on that.
>
> DR. JENKINS: Do you have anything built into your proposal that would
> say, okay, we get to that four, six, whatever month time point and
> find that the results aren\'t what you hoped to see, what do you do
> then? Do you continue on the same level of your launch scale or do you
> intervene but then proceed to the broader launch that you are
> proposing?
>
> DR. HADDOX: Retrain the sales reps if there is an issue that we are
> concerned with or the agency is concerned with, and not expand until
> we have satisfied that issue.
>
> DR. KATZ: Dr. Strom, you were next.
>
> DR. STROM: I am very impressed by the effort that has been put forth.
> As a tangential thing but important, I think it is very important that
> it be public, that the data that emerge and your advisory committee
> sees be available, be published, not be kept secret.
>
> But I still am left with two major concerns about the plan as it is
> proposed. One is concern about the lack of data that there is a unique
> benefit to these longer-acting drugs. Combine that with the fact that
> there clearly is a unique risk, particularly in the very high dosage
> forms here, makes me worried. So, what I would suggest is that, (a)
> there certainly shouldn\'t be a 32 mg formulation yet, which would be
> the highest risk and I don\'t see any reason for that; people can
> always take two 16 mg.
>
> I like the idea of phased marketing. Perhaps the initial phase of the
> marketing should be at the lowest dose only and it should go on long
> enough to generate both data that there is some advantage, as a
> separate set of studies, to patients of using these formulations as
> opposed to the immediate-release formulations and that there isn\'t
> substantial abuse of the lower dose formulation. Because if there is
> already substantial use of the lower dose formulation using the
> mechanism of data collection that are being proposed, then going on to
> the higher dose formulations is going to be even worse.
>
> DR. KATZ: Dr. Rose, you are next.
>
> DR. ROSE: I guess I am going to be very much agreeing with Dr. Strom.
> I agree that a one-year initial phase is far, far superior to the four
> months. I don\'t think four months is enough at all to collect any bit
> of information.
>
> I believe that what we should expect after a year is two sets of just
> statistics. The first set would be a knowledge and documentation of
> adverse events of diversion and abuse, which is going to happen; it is
> just a matter of how much, how severe, etc. Then, the other set is the
> benefit information on appropriate patients treated appropriately.
> Then take those two bits of information and decide what the
> risk/benefit ratio is. Because we could have a very great benefit but
> if the risks are far superior to that, then I just don\'t think it is
> a wise drug to have on the market. So, I would like to see these two
> phases come together at the end of a period of time that is
> significant.
>
> DR. KATZ: So, you are suggesting more than just extending the duration
> of the first phase to a year, but you are suggesting that continuing
> into the second phase should be based upon data that relate to the
> outcomes of interest rather than surrogates like message integrity. Is
> that what you are saying? Is that what you were saying, Dr. Strom?
>
> DR. STROM: That is exactly what I was saying.
>
> DR. KATZ: But it sounds like you are both also saying something more
> than that, which is that measuring safety is not sufficient to make a
> decision about the risk/benefit analysis of this drug but that there
> has been an unsatisfactory amount of data on the benefits of this
> medication over immediate-release formulations, and that you could
> only interpret the safety data, whatever it is that comes out, in
> light of clinical trials that relate to relative efficacy, which is a
> whole separate kettle of fish and we understand that; you are not
> going to get that from a patient registry or an observational
> database.
>
> DR. STROM: Exactly correct. The other thing I would add is that in
> that first phase it should only be available in lower dose.
>
> DR. KATZ: Thank you. Dr. Shafer, you are next.
>
> DR. SHAFER: Several points, first off, I commend Purdue for putting
> the program together. I think actually it is a very meritorious
> program. If asked right now just to vote up or down on the program
> presented, I would vote to support it.
>
> Number two, I absolutely support one year being a better program, and
> I think that that is an important message that you are hearing
> uniformly from the committee. If you want to look at, you know, bodies
> hitting the pavement, I have concerns, both in our conversations here
> and in the conversations we have not had during breaks\--
>
> \[Laughter\]
>
> \--that in four months you are not going to see the really serious
> morbidity and mortality that we are concerned about, which you might
> see at one year. I have heard nothing about how the program interfaces
> with prescription drug monitoring programs run by the states. It is
> kind of mysterious because there was a lot in our packet about that
> and I am surprised that that has not shown up in our discussions and I
> would like that to be addressed.
>
> I would like to see an educational component to it, talking about the
> risks of opioids in general and some of the unique issues with both
> sustained release and then with sustained-release Palladone. I don\'t
> know how to put teeth in that to be sure that the vast majority of
> practitioners get the educational program in order to practice without
> being formal. I don\'t know how you put teeth in to make sure that
> that happens and that people actually sign up and get training, but I
> think that would be an important addition to the program, particularly
> since we have heard that the DEA will not be able to make that happen
> as part of registration for your license any time soon.
>
> Lastly, we are not really coming at this [tabula rasa]{.underline}.
> There are data from Canada and the U.K., where the drug is available,
> and I would just like to know what is the experience there.
>
> DR. KATZ: That seems to be a good question. Laura, do you have any
> information about the experience in other countries?
>
> MS. NAGEL: No, I don\'t.
>
> DR. KATZ: Anyone from FDA, anybody know that?
>
> DR. HADDOX: The adverse event experience in the two countries
> mentioned has been very, very little abuse.
>
> DR. KATZ: Numbers?
>
> DR. HADDOX: I don\'t have the numbers. I am not in charge of drug
> safety, but we can probably get them for you.
>
> DR. KATZ: Maybe, Dave, you could also clarify for us how long the
> medications have been available in those two countries.
>
> DR. HADDOX: I would have to ask my colleagues about that.
>
> DR. GOLDENHEIM: One formulation\--
>
> DR. KATZ: Go to the mike, if you could, and introduce yourself,
> please, also.
>
> DR. GOLDENHEIM: Paul Goldenheim, Purdue Pharma. A different
> controlled-release formulation of hydromorphone has been on the
> Canadian market\--we will get you the exact number but I am going to
> guess for about six years. In terms of the United Kingdom, the same
> formulation that is on the market in Canada, slightly different from
> this one, has also been on the market, I would guess, for
> approximately six years.
>
> I think that there is something also that is important to recognize, I
> think any kinds of restrictions that the committee is thinking of
> placing on Palladone would need to be applied to all such medicines in
> this class and I have to say I very much fear what Herb Kleber talked
> about on his last slide, that we risk grave unintended consequences to
> patients from the kinds of things that we are talking about here.
>
> We have a very serious approach to risk management. We want physicians
> to be educated. We take this responsibility very, very seriously and
> are very worried about the consequences of this to patients. It is not
> always easy to say just take two 16 mg capsules. There are some people
> who need three, four, five, six capsules a day. We have had a lot of
> negative feedback about these issues from patients and from their
> physicians and I think we have to proceed very carefully here.
>
> DR. KATZ: Thank you for your comments. I think your point is well
> taken that for any intervention that is considered the potential
> downside needs to be considered as well. I think we have been hearing
> that for two days now. Dr. Baxter is next.
>
> DR. BAXTER: Thank you very much. Once again, I would like to chime in
> that I applaud Purdue because the RMP is very, very good and I think
> that the program is very good.
>
> But I think that in order to answer this particular question we need
> to try to manage the risk up front and the best way to do that, in my
> opinion, is through the labeling, and perhaps we could add some of the
> suggested wording that there are some patients that are at high risk
> for abuse and those patients would require additional monitoring.
>
> I like the idea of education and some sort of registration. Basically,
> by educating physicians or other providers and by having some form of
> registration, no matter how simple, we would give some would be rogue
> prescribers at least a moment to pause before they start writing
> prescriptions willy-nilly.
>
> DR. KATZ: Dr. Bril?
>
> DR. BRIL: I think that this is a major program as planned by Purdue
> and is probably unlike anything else that has been done in a roll-out
> to date. But what I have heard and seen from the last two days is that
> all of the databases and information-gathering systems have their
> flaws and limitations. A lot of the data was given in numerator form
> so you really didn\'t know what it meant. A lot of the deaths were in
> people who had taken multiple agents so you don\'t really know what
> was causing the death in the drug overdose people for sure. You don\'t
> know if it was OxyContin or if it was the combination, or whatever
> they were on.
>
> So, I am not sure that the plan will actually limit the abuse and make
> the slower-release form safer but at least you will get a lot of
> information that you haven\'t had to date and perhaps that will modify
> what happens in the future. It is a start. But I don\'t know how you
> could say that it will work or achieve its goals because there is no
> evidence that even education, for example, will work. So, this is a
> start and it is quite an intense and aggressive start, I would say,
> but whether it will actually work I don\'t know.
>
> I don\'t know whether four months\--I think that is very short but, I
> agree, and 12 months seems more reasonable. But this is quite a step
> forward.
>
> DR. KATZ: Dr. Dworkin?
>
> DR. DWORKIN: It sounds to me like there are two things we really,
> really know. One is that we have no data and the other is that it is
> going to take DEA at least three, maybe five, maybe more years to put
> in place some registration system combined with education. Given that,
> I can\'t think of any reason why it doesn\'t make a tremendous amount
> of sense to have a 12-month roll-in where for 12 months all of the
> data that we heard about this morning are collected, RADARS etc., but
> that within that 12 months of the launch, as Dr. Aronson said, the
> first phase promotion be severely be limited to, say, pain specialists
> and oncologists and at the end of the year we will have all the data
> we have been hearing about for two days that we don\'t have today.
> Then, the next step of the launch will depend on the data.
>
> DR. KATZ: We have heard a lot of comments on the data and concerns
> that it might be delayed, or what-have-you, but does anyone have any
> comments on whether the intensive data collection and the sorts of
> databases that will be developed address the issue, whether they are
> adequate to the task at hand? Do they give us the information we need?
> Dr. Gillett and Dr. Strom.
>
> DR. GILLETT: We have an inverted pyramid here in which we are going to
> have a tremendous body of data generated by a very aggressive and
> forthright program that I really appreciate, but it rests on the
> security and integrity of the formulation, which is proprietary, not
> well explained and certainly capable of being fiddled with\--it can be
> fiddled with outrageously and that is where we are going to have this
> data, resting on the point of this pyramid. I think discussing how
> long we wait until the top falls over is not maybe mundane or not
> proper.
>
> DR. KATZ: So what are you trying to say?
>
> DR. GILLETT: That we really need to have a discussion of the quality
> of this formulation, of its integrity and how much we can rely on that
> to base our decision of what kind of data to gather.
>
> DR. KATZ: I want to make sure I catch your point. Are you saying, if I
> can paraphrase and not to be dramatic, all the data in the world
> isn\'t going to make a difference if the formulation itself can be
> easily compromised and be associated with abuse?
>
> DR. GILLETT: Yes.
>
> DR. KATZ: That is what you are saying? Dr. Strom?
>
> DR. STROM: Yes, I think the data that will be gathered here is really
> not perfect but I can\'t think of anything better. I think Purdue is
> doing an enormous amount to do it. I think something like a year makes
> sense. I think the criteria should be database criteria though rather
> than time based, and it may be that it can be done in a year and maybe
> it takes 18 months or two years. If it can be done in a year, great,
> but if these data were gathered and available a year from now, along
> with an estimate of relative efficacy based on a lower dose
> preparation I would be much more comfortable about making a
> risk/benefit judgment to release it in total.
>
> I do agree with the company that restricting one drug different from
> the other drugs of the class is problematic. I think a year from now
> or whenever those data are available, the position I would prefer
> would be to put this drug in line with the other drugs in the class
> either with all of them more restricted or this one much less
> restricted, depending on what the data show.
>
> DR. KATZ: If this data is going to have implications for multiple
> different companies that produce these medications do you think that
> the burden of data collection and the resources involved should also
> be shared among different companies with all the other implications
> that come from multiple source data?
>
> DR. STROM: I certainly would have no problem if other companies wanted
> to be part of it. I don\'t know whether or not Purdue would want that.
>
> DR. KATZ: Dr. Leiderman?
>
> DR. LEIDERMAN: The question came up about experience in the U.K. and
> Canada and I just wanted to point out that the indication in the U.K.
> at least is for severe pain in cancer patients. So, it is a whole
> different experience.
>
> The second sort of question I want to raise or the point I want to
> make is that we conceive of risks and misuse to various parties, and
> that includes not only the patient and this sort of mythical abuser,
> but there are also family members, particularly vulnerable children
> and adolescents. And, I want to remind the committee that there have
> been different kinds of tools brought to bear for similar products.
> For example, you have the Actiq risk management plan included in your
> background materials and that product has many of the same risks, and
> there were specific concerns about children having access to that,
> partly because of the attractiveness of that formulation but also
> simply because of the very high dose. So, that point I think needs to
> be brought up.
>
> Then, since we have alluded to the Xyrem or GHB risk management plan
> and discussion about that, similarly, there was very much concern
> about how the formulation as well as the dose, concentration,
> quantities factored into the risks to other household members,
> particularly children and adolescents. So, I want to throw that into
> the thinking.
>
> DR. KATZ: So, you are asking us to consider a second category of
> risks. Whereas we have mainly been concerned about addiction and
> abuse, you are asking to consider unintentional access to children and
> other vulnerable individuals. Dr. Shafer, you were next.
>
> DR. SHAFER: I would just like to mention I just looked up the Canadian
> doses that are available. The dose forms that are available in Canada
> are 12, 16, 24 and 32, the same as proposed here. I would like to
> chastise both the company and the FDA and DEA that we don\'t have six
> years of data on the Canadian and British experiences, which I think
> would be very germane to our discussions. It would have been very nice
> if we had known what they actually saw with six years of experience so
> we could have some idea whether we are really going to have bodies on
> the street within a few weeks of this drug being introduced.
>
> DR. KATZ: Before you go on, would any of the multiple corporate and
> regulatory agencies that were just chastised care to respond to that?
> Dr. Goldenheim, please?
>
> DR. GOLDENHEIM: Yes, I am volunteering to be publicly chastised. Point
> well taken. I guess the reason that we didn\'t think about it is
> because it is a different formulation and typically we tend to think
> about these things as different formulations. It is a 12-hourly
> formulation, a different technology. There would be different issues
> with it but, nevertheless, point well taken. We will get the data to
> you. I don\'t think we know of any, but we will check, overdose
> deaths.
>
> The fact though is that prescription drug abuse however, as I am sure
> the committee recognizes, is a different kettle of fish in this
> country than it is in Canada and the U.K., at least according to
> anecdotal reports and this is yet another area where, frankly, there
> is precious little data. So, you know, bottom line in terms of safety
> of patients, there aren\'t any significant or unexpected issues. The
> episodes of abuse, of diversion, of overdose are few, if any but they
> are different environments.
>
> DR. KATZ: Thank you, Dr. Goldenheim. Dr. Jenkins?
>
> DR. JENKINS: Yes, just to put that in context, could you comment on
> what the experience has been with OxyContin in Canada so that we can
> understand how the relevant experience with sustained-release
> hydromorphone in Canada might relate to the United States? If you
> haven\'t seen much abuse of OxyContin in Canada, then the Canadian
> experience may not be very helpful.
>
> DR. REEDER: Robert Reeder from Purdue Pharma. The product OxyContin is
> on the market in a number of countries, including Germany, U.K.,
> Canada. The abuse pattern is very minimal in those countries. There
> are some episodes of abuse. For example, in Europe less than 20 on the
> continent. The abuse pattern is vastly different than in the U.S.
>
> DR. KATZ: Thank you, Dr. Reeder. Dr. McLeskey, you were next.
>
> DR. MCLESKEY: I would like to echo what has been stated by so many
> here today, that Purdue should be complimented for bringing this risk
> management program forward in its current form. In fact, I will quote
> Dr. Hertz who said earlier on who said that this is the best effort so
> far that she has seen among products with risk management programs
> brought forward to the FDA.
>
> On the other hand, I would just make one comment. I believe a comment
> was made that if some kind of restriction is applied to Palladone that
> that should be, therefore, to future approval for all opioid
> analgesics. I would suggest, just as the data from Canada for example
> may not be applicable to the data from the U.S. and, in fact, it was
> thought to be potentially so different it wasn\'t presented, I would
> suggest we extend that information and apply it in the same context
> that for each of these agents, each of these new analgesics\--I
> believe I would speak for industry at large, all the companies working
> in this area\--that individualized consideration should be applied to
> each of those and an evidence-based decision made.
>
> DR. KATZ: Dr. McLeskey has been very forthcoming about his potential
> conflict of interest prior to coming to this meeting, both in writing
> and verbally, and maybe it would be an appropriate time for you to
> mention that to the group.
>
> DR. MCLESKEY: I am happy to. I have been especially quiet during this
> meeting, for those of you who have seen me at other meetings, and that
> is because I am trying to be very respectful of the industry position
> in general and not represent any kind of conflicted view that might
> result from the efforts of my own company, Abbott Laboratories, in
> this particular market area in which we are also working.
>
> DR. KATZ: Dr. Skipper, you are next.
>
> DR. HERTZ: I am sorry, I just want to clarify\--I have already been
> misquoted once in the \"Pink Sheet\" and would not like to have it
> happen again. I was referring only to efforts for modified-release
> opioid risk management programs. It was in no way a commentary on risk
> management across anything beyond that.
>
> DR. KATZ: Clarification accepted. Dr. Skipper?
>
> DR. SKIPPER: Thank you. If we are going to release this drug in the
> United States, it seems to me it would be prudent to release it with
> the restriction that it only be used in malignant pain, as they did in
> the U.K. or Canada, and then advance it later if we see no problem. I
> would recommend that.
>
> DR. KATZ: Thank you. Of course, that is a huge can of worms that we
> could talk about if we need to. I just wanted to ask one more
> question, before we leave the subject of the data collection entirely,
> to try to resolve what seems to be a paradox through this meeting. One
> of our primary concerns is what happens to the people that we
> prescribe this medication to in terms of negative outcomes, yet, I am
> not sure\--and maybe the rest of the committee or the sponsor can help
> me\--I am not sure that I am seeing that those patients are actually
> going to be monitored for the negative outcomes that we are concerned
> about. It seems like we are monitoring primarily abuse and negative
> outcomes as they occur in the community from whatever source. I wonder
> if individuals on the committee feel that it would be an appropriate
> part of a risk management program to actually monitor our patients for
> the negative outcomes that we are concerned about. Dr. Baxter and then
> Dr. Crawford.
>
> DR. BAXTER: That is exactly what I was saying and that is what I
> meant. Maybe I wasn\'t clear enough but, certainly, those patients
> that are going to be put on this medication should be watched, and
> they should be monitored, and the form of monitoring is up for
> discussion. But I think that it is very important that as we begin to
> prescribe this medicine we watch our patients and be prepared to
> intervene where intervention is necessary.
>
> DR. KATZ: Dr. Crawford?
>
> DR. CRAWFORD: Thank you. I think not only is it appropriate, I think
> it should be mandatory because, as an example, I never heard an answer
> to Dr. Gillett\'s question in terms of message integrity of the
> patients. The proposed patient package insert says do not crush,
> dissolve or chew. Could it or would it be confusing to those same
> patients to be told that they could sprinkle it on their food? So, I
> think a lot of those issues go hand-in-hand.
>
> DR. KATZ: Yes, Dr. Cicero?
>
> DR. CICERO: I am Dr. Cicero from Washington University. I am a
> consultant for Purdue. Obviously I have a conflict of interest that
> you need to recognize.
>
> I think it is really important to point out there is not a blank slate
> here. I think we heard some comments yesterday about older, more
> established programs. One of those was Tramadol. It was a
> postmarketing surveillance program approved for Tramadol in 1984 and
> data was gathered systematically over that entire period of time about
> what constitutes a prescription drug abuser. So, there are data. There
> are four peer reviewed publications on this where we have documented
> what these people look like. So, we have those data there.
>
> More importantly, the FDA yesterday failed to indicate that there were
> two additional FDA meetings after \'94 in which the original decision
> was revisited, to take a look at the data and see if the data actually
> upheld the decision that was originally made. I see no reason why a
> similar model can\'t be applied in this situation. I think you can, in
> fact, establish programs.
>
> The problem we have with all of the prescription drug abuse, and NIDA
> has put out an RFA trying to get proposals for this, we don\'t know
> what people who abuse prescription drugs look like. We know very
> little about them, except that for the Ultram experience\--again,
> published data\--they have an extensive history. By and large, those
> who have abused it, 97 percent, have a history of strong opioid abuse.
> They tend to be white primarily as opposed to ethnic minorities that
> you see with some other drugs. They tend to be of a little higher
> socioeconomic class. We are beginning to understand a little bit about
> this patient population.
>
> I think by extension with OxyContin the attempt was really to get some
> baseline information on OxyContin so that if Palladone does get
> released there are things in place to actually begin to look at it.
>
> We talked about interventions today and, unfortunately, we are a
> little bit caught short here, just as the NIDA proposal was caught
> short. We don\'t know what we are looking yet. These are not patients
> generally, they are a subset of people whom we need to know how to
> target and how to intervene if possible. It may not, in fact, be all
> that easy to intervene. We won\'t know that until we study a little
> bit more about the population.
>
> What I worry about is if we throw up our hands and say we are not
> going to get anywhere with this; we don\'t know what is going on. We
> tend to be focusing on that aberrant three or four percent of the
> people that are suffering from the risks of it and, again, the pain
> patient is being ignored here and I can\'t help but worry about that.
> But, again, this isn\'t a blank slate. We have some information. We
> need to gather more information.
>
> DR. KATZ: thank you. Dr. Dworkin?
>
> DR. DWORKIN: Yes, I would just like to ask Dr. Cicero a question. It
> has been proposed here that there be a phased roll-out of the drug and
> that for 12 months the RADARS and all these other data be collected.
> Setting aside Dr. Katz\' issue about a large, simple trial which I
> think is a complicated trial, but if we just collect the RADARS data
> etc., that we heard this morning, for 12 months, do you feel, based on
> your experience with Tramadol, that that would be enough data to
> provide the kind of information you have so thoroughly documented for
> Tramadol?
>
> DR. CICERO: I probably won\'t be a consultant tomorrow so I will
> answer the question. Yes, I do believe that in a 12-month period of
> time you could get that data, particularly since we already have
> mechanisms in place. This is rolling for OxyContin; it has been
> accumulating for six quarters now, and the whole plan was to expand it
> to include Palladone as it comes along. We can easily expand it and we
> will get data to look at within 12 months. We will have data on the
> Key Informant Network; we will have data on the diversion; we will
> have data on poison control; most importantly, where do these
> coalesce? Where do we see multiple signals so that we can actually go
> in there? I say \"we\" because it has to be a joint effort between the
> company and I think the EAB. I think it has been agreed we need to go
> in there, take a look at it with all the expertise we have and say,
> okay, we have multiple signals coming from this little metropolitan
> area, what is going on? Where is the drug coming on? You have heard
> speculation throughout the two-day meeting, it is being stolen; it is
> coming from script doctors. We don\'t know that. Everybody is making
> their best calculated guess. We need to find out about that.
>
> But the way I look at this whole thing is first give us a signal that
> there is a problem, then let us go in and see what the nature of that
> problem is so we can try to figure out what the heck we can do. Maybe
> we will come back in 12, 18 months and throw up our hands and just say
> it is an endemic problem. We don\'t know what has occurred. As Herb
> was talking about today, maybe there is something about our population
> that, for whatever reason, for the last hundred years we can\'t quite
> seem to get rid of this problem of prescription drug abuse.
>
> But in answer to your question\--I was expounding here a little on
> public health issues, but I think fundamentally, yes, we can get the
> data. Twelve months, I don\'t know if that is magical, or 18 months.
>
> DR. KATZ: Thank you, Dr. Cicero. I hear you. Thanks. It is the
> ten-minute mark until the end of our meeting so I would like to turn
> to the FDA and ask them for their guidance on how you would like to
> use this time. Are there any specific issues that you would like us to
> focus on?
>
> DR. MEYER: Well, I would say that we have obviously skipped over some
> questions related to risk management so I think if there are other
> elements of risk management that people would like to point out for us
> to consider, not just for Palladone but for all of the
> extended-release opiates, it would be important for us to hear that. I
> am not sure we are totally done with the discussion of Palladone too,
> so we would certainly take more points or things that might be
> considered for the risk management of Palladone specifically.
>
> DR. KATZ: So, anything specific, Dr. Meyer, or just general comments
> about the risk management approaches and Palladone?
>
> DR. MEYER: Again, there are several elements of the risk management
> plans that were a sub-part of this question, and even some that were
> not actually raised or discussed yesterday, like further research
> needed. We have heard some questions put out today that I think would
> fall into that category bit since we only have ten minutes I don\'t
> want to focus it, but if people have burning things that they think
> are very important for us to hear, we would need to hear those.
>
> DR. KATZ: I think what I will do then is use my discretion to pick up
> on something that Dr. Shafer brought up earlier, which is the
> potential usefulness of prescription monitoring programs. Someone
> correct me if I am wrong, I think something like either 17 or 19
> states so far have electronic prescription monitoring programs. Some
> states have more proactive programs where information is provided to
> physicians on the utilization by their patients of opioids from
> whatever pharmacy, whatever source over a certain period of time. In
> other states the data is only available for law enforcement.
>
> We have heard a lot from our DEA colleagues about things like doctor
> shopping, multiple prescribers, things like that, that presumably
> could be identified through prescription monitoring programs and I
> wonder if people would are to comment on whether such programs could
> have usefulness in postmarketing surveillance efforts, or in research,
> or in any other application help us better understand the safety
> issues behind these drugs. Laura, go ahead.
>
> MS. NAGEL: It is one of the other areas where the DEA and the FDA
> agree. We are both proponents of the prescription monitoring programs
> in each state. We feel very strongly that they have been found to
> assist the physicians even more than they actually assist law
> enforcement. They are able to give the physician some sense of
> confidence if he or she questions someone that might be a doctor
> shopper to ensure that they are not going to several places. If law
> enforcement has a specific target, they are able then to go in and
> determine whether there is more investigation that needs to be done.
>
> Mr. Rogers, who is here from Kentucky, put I think 10 million dollars
> in the budget for states to come and get grants. They feel in Kentucky
> that the program at the state level in Kentucky very much helped them
> identify their Oxy problem when they did. Without it, they think it
> would have gone longer and been worse. So, we are tremendous
> supporters and, with the FDA, intend to try to promote it as best we
> can state by state.
>
> DR. KATZ: Our drug control program in the Commonwealth of
> Massachusetts has been one of the recipients of that Harold Rogers
> grant and we are just starting a project now to go through our
> databases. In Massachusetts, for better or worse, we only track
> Schedule II opioids but we are starting to work on validating
> algorithms to detect, hopefully accurately, some of the issues that we
> are talking about, as well as to monitor patients for development of
> untoward complications that may require further management.
>
> There was a big discussion in Massachusetts, as you might imagine,
> about patient confidentiality and privacy and that whole thing, but
> since 1992 when the program was implemented, actually people from all
> different stakeholder viewpoints have been very satisfied that those
> concerns have not become problematic.
>
> Any other comments about the utility of prescription monitoring
> programs? Yes, Dr. Gillett?
>
> DR. GILLETT: I just wanted to encourage them to continue to evaluate
> these programs as they go along in ways that are open, transparent and
> as precise as they can be made because they are teaching a lot of
> people how to do something well and I think that is really important.
>
> DR. KATZ: Dr. Shafer?
>
> DR. SHAFER: Why doesn\'t the RADARS system incorporate it?
>
> DR. KATZ: That sounds like a question for our sponsor. Dr. Haddox?
>
> DR. HADDOX: We don\'t have statehood. These are legislative programs.
> As I answered one of the questions this morning, we have been
> encouraging these. We have been helping actually with legislative
> language. The key here I think is well-designed programs. We believe
> that programs should monitor all Schedule II through V controlled
> substances because of the squeezing of the balloon that Dr. Kleber
> talked about and the paper by Weintraub that described the New York
> experience several years ago with some scheduling of some things and
> restrictions on some and not on others.
>
> Another part of well-designed is to allow exactly what was talked
> about here, that is, have a provision in the legislation to allow for
> scholarly pursuits. This would be blinded. It wouldn\'t be specific
> information so you couldn\'t identify a patient but aggregate data to
> look at trends, and so forth, and make these things available. Some
> states, as Dr. Katz mentioned, are more proactive about this than
> others. But we do support well-designed, electronic, low barrier
> prescription monitoring programs for all controlled substances.
>
> DR. SHAFER: But you don\'t have access to the data.
>
> DR. HADDOX: It depends on the state. We actually have two requests in
> to two states right now, and we will get whatever data they will share
> with us. Some have issues about how they will share the data in and
> out of state, etc.
>
> DR. KATZ: Ms. Nagel?
>
> MS. NAGEL: Just very quickly, one of the grants this year is to do an
> assessment of the programs and to try to check the data to see if we
> can come back and explain how they are good or not. So, we also feel
> very strongly and we need to put that forward for everyone to see.
>
> DR. KATZ: In the two minutes left I just wanted to get one other
> question out for people to consider. It seems like it has been
> generally accepted that any good risk management effort or tool will
> target the problem that it is trying to target but not have an
> excessive negative effect on appropriate opioid prescribing. Yet, I
> haven\'t heard any suggestions and I don\'t think we have discussed in
> the last two days how we can measure the extent to which opioid
> prescribing is appropriate, or has been negatively impacted by any
> risk management intervention. It concerns me that at the end of the
> day we may have information on the negative outcomes we are trying to
> prevent but not information on appropriate opioid prescribing, which
> we are trying to encourage and don\'t want to diminish. Does anybody
> have any thoughts on whether I am completely off base or whether we
> should consider ways of measuring the degree of appropriate opioid
> prescribing and incorporate that into our assessment of the overall
> pros and cons, overall results of any risk management effort? Dr.
> Rose?
>
> DR. ROSE: Well, when I talked earlier about wanting two sets of
> information at the end of a provisional year, basically my assumption
> was that in getting information on the benefits for appropriate
> patients that was inherent in what I was talking about. We want to
> know what good does it do these patients if they are appropriately
> chosen; what other bad things does it do to the appropriately chosen
> patients. So, I think that is part of what I was saying we should
> expect.
>
> DR. KATZ: Dr. Bobek?
>
> DR. BOBEK: I was wondering if the pharmacy education piece as well as
> the physician education piece is being considered by the DEA. We are
> also highly involved in drug diversion and dispensing of these agents.
>
> MS. NAGEL: We were targeting the physicians initially, not all
> registrants, which would include the pharmacies, and down to the
> pharmacist.
>
> DR. BOBEK: I was wondering if it is also possible if a pharmacy can
> document the indication of the opioid use at the time of dispensing,
> so, it is used for back pain; used for postoperative pain, and that be
> in your state generated database so you can actually run data to see
> are these inappropriate prescriptions potentially, and use that in
> some sort of, you know, physician education piece as well. I didn\'t
> know if that was a possibility.
>
> MS. NAGEL: To the best of my knowledge, the indications to be included
> in that haven\'t been contemplated.
>
> DR. KATZ: Any other comments about how one might measure rates of
> appropriate utilization? Dr. Strom?
>
> DR. STROM: Yes, I think it is a great idea and makes a lot of sense,
> in addition to sort of a randomized trial to find out benefit, to find
> out from population point of view whether it works. I think it would
> take a lot of thought about how to do it correctly and, you know,
> survey kind of methods would certainly be one way to do it. Another
> would be, for example, to survey people who have particular diseases
> that are commonly painful and look to see what proportion of them are
> being treated with analgesics, and then maybe survey a sub-sample of
> them to find out what proportion of them are being treated
> successfully with analgesics and, ideally, even to do this at the
> beginning and the end. For example, if there was a year phase-in to
> this risk management plan, to do it in the year when the drug isn\'t
> yet widely available and to do it a year or two later, after the drug
> is much more widely available. But I think the idea of having data on
> benefits to balance the data on risks is critically important.
>
> DR. KATZ: I am going to take the last 60 seconds to summarize what I
> think we have heard in discussion, although that is not an easy job
> and if I get anything wrong somebody can jump up and down and correct
> me.
>
> What I have heard is that it seems to be universal that people
> feel\--well, maybe not universal, Dr. Strom, but people feel education
> is important and\--
>
> DR. STROM: Just a second, can I just speak quickly? I don\'t want to
> be misunderstood. Education has been shown repeatedly not to work in
> voluntary education but I agree with the idea of education as part of
> the DEA change which, in turn, would apply to all narcotics. So,
> don\'t take me as an exception.
>
> DR. KATZ: So, you took the words out of my mouth. People feel strongly
> that education is appropriate. People felt even more strongly that the
> real missing piece in education is some way of putting teeth into it,
> as you said; that it can\'t be escaped in order to prescribe
> medications. While a legislative effort might take a long time, we
> should think creatively about shorter-term solutions for making that
> happen.
>
> Next, in terms of the labeling, we heard what seems to me a consistent
> suggestion that it might be appropriate to consider for the label some
> indication about assessment of the risk of the patient for negative
> outcomes, and some suggestion that enhanced monitoring for those
> patients might be appropriate, although collecting data on the
> usefulness of those interventions would be equally appropriate so that
> we can monitor the results of that over time.
>
> People seemed to feel pretty uniformly that the first phase of the
> launch might be better off extended. All different sorts of times came
> up. A year seemed to be the mode number, but I think people\'s real
> concern is that we had data on actually the outcomes of interest
> rather than on surrogate measures, rather than to pick an
> arbitrary\--you know, should it be 11 months, or 9 months or 18
> months.
>
> I heard that as far as the ultimate data that is obtained from the
> RADARS system, it seemed like people were extremely interested in
> being able to know ultimately what the source of diverted or abused
> drugs is. It seemed like that came up as a consistent, terrible
> question mark that we still have and ultimately with the RADARS system
> or other aspect of the program we ought to be able to make statements
> about the actual sources so that we can ultimately, in the next
> iteration of this meeting, be more rational in our selection of risk
> management approaches.
>
> People seemed to feel that it was appropriate to understand better
> another big question mark, which is what is the complication rate of
> these negative complications in our patients, and that any risk
> management program ought to not just skip over the patients to the
> community but also somehow consider what is happening with the
> patients and we, I think, made no progress on whether that should be a
> large, simple trial, or a registry, or another kind of surveillance
> program. That is something that will have to be considered.
>
> Also, there was a lot of discussion that, despite the fact that we are
> here aegis of considering modified-release opioids and in particular
> Palladone, it didn\'t seem like anybody thought that the other opioids
> were free of these concerns, and a number of people expressed the
> squeezing of the balloon analogy where, yes, we can maybe clamp down
> on something here but, unless we know what is happening in another
> part of the balloon, we may be wasting our efforts or even making the
> problem worse.
>
> Then, finally, in the last waning moment of our conference we heard
> that prescription monitoring programs could be useful parts of risk
> management, both from the perspective of research and understanding
> what is going on, monitoring patients, monitoring for doctor shopping
> and other law enforcement issues, and that these will need to be
> explored.
>
> Finally, the last bit was that if we are going to try to introduce
> measures that decrease complications, such as diversion, addiction,
> etc., we need at the same time to make sure those measures are not
> decreasing appropriate opioid prescribing. We need to consider ways of
> measuring that so we really do have Dr. Rose\'s two sides of the
> equation on how to do that, we did not consider in any detail but it
> would be worth considering.
>
> That is what I heard. Did I get anything completely wrong or leave out
> anything absolutely essential? Any final comments or questions from
> the FDA?
>
> DR. MEYER: I would just like to thank everybody. This has been\--I
> guess diversity would sort of encapsulate this meeting because we have
> a diverse background of the rather large committee that served. We
> have a diverse effort on the part of the government, having folks from
> the DEA and several areas of HHS and even several areas within FDA. We
> certainly appreciate the public commentary as well. I think we got a
> lot of very useful discussion and advice out of it. So, we certainly
> thank each and every one of you, and thank the sponsor as well for
> your participation.
>
> DR. KATZ: Let me add my thanks to the advisory committee for helping
> me get through this and get some information to the FDA, and also
> again to the sponsor who, I think everybody agreed, has put together
> the best program for this class of agents that is around. It is
> clearly a major step forward and I only hope that our input will help
> make it even better and more useful ultimately for our patients.
> Adjourned.
>
> DR. DWORKIN: And I want to thank you, Nat, for doing a splendid job of
> chairing this meeting and keeping us all on track.
>
> \[Applause\]
>
> \[Whereupon, at 5:00 p.m., the proceedings were adjourned.\]
>
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