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`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF THE ASSISTANT SECRETARY FOR HEALTH
`NATIONAL INSTITUTES OF DRUG ABUSE
`CENTERS FOR DISEASE CONTROL AND PREVENTION
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`Role of Naloxone in Opioid Overdose
`Fatality Prevention
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`Thursday, April 12, 2012
`8:30 a.m. to 5:30 p.m.
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`FDA White Oak Campus
`White Oak Conference Center
`Building 31, The Great Room
`Silver Spring, Maryland
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`C O N T E N T S
`AGENDA ITEM PAGE
`Welcome and Opening Remarks
` Peter Lurie, M.D., M.P.H. 5
`Panel 1 – Naloxone Safety and Effectiveness in
`Treating Opioid Overdose
`Moderator
` Bob Rappaport, M.D. 15
`Populations at Risk
` Len Paulozzi, M.D., M.P.H. 17
`Public Health Interventions
` Nicholas Reuter 33
`Naloxone: Effects and Side Effects
` Gregory Terman, M.D., Ph.D. 54
`Questions and Answers 68
`Panel 2 – Opioid Overdose Interaction with
`Naloxone in Extra-Medical Settings: Review and
`Examples of Current Practices
`Moderator
` Wilson Compton, M.D., M.P.E. 77
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`C O N T E N T S (continued)
`AGENDA ITEM PAGE
`Overview, Criminal Justice and
`Other Special Settings
` Ingrid Binswanger, M.D., M.P.H. 82
`Bystander Overdose Education and
`Naloxone Distribution in Massachusetts
` Alex Walley, M.D. 101
`Project Renaissance: Overdose Prevention among
`IDUs in Kazakhstan
` Nabila El-Bassel, M.D. 120
`Questions and Answers 137
`Panel 3 – Product Development Issues
`Related to Naloxone
`Moderator
` Douglas Throckmorton, M.D. 158
`Naloxone for Outpatient Use: Data Required to
`Support an NDA
` Sharon Hertz, M.D. 164
`Expanded Access: OTC Status
` Andrea Leonard-Segal, M.D. 174
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`C O N T E N T S (continued)
`AGENDA ITEM PAGE
`Development and Marketing of
`Needleless Naloxone
` Dan Wermeling, Pharm.D. 191
`Ethical and Regulatory Considerations for
`IN Naloxone
` Robert Nelson, M.D. 214
`Questions and Answers 231
`Open Public Hearing 252
`Panel 4 – Social and Legal Aspects of
`Wider Naloxone Availability
`Moderator
` Peter Lurie, M.D., M.P.H. 307
`Lessons Learned from Implementation of
`HPV Vaccine
` Gregory Zimet, Ph.D. 309
`Panel Discussion 322
`Questions and Answers 355
`Closing Remarks 395
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`P R O C E E D I N G S
`(8:37 a.m.)
`Welcome and Opening Remarks
`DR. LURIE: Good morning, everybody. My
`name is Peter Lurie. I'm a senior advisor here in
`the Office of Policy and Planning here at FDA, the
`Office of the Commissioner. And I'm pleased to
`welcome you this morning to our meeting on the Role
`of Naloxone in Opioid Overdose Fatality Prevention.
`We put on a lot of meetings here at FDA. I
`think this one is cut from a different cloth. And
`I think for all of us, it is a very exciting
`opportunity for us to engage in conversation with
`you about this interesting and important topic.
`This meeting is put on collectively by the
`FDA, by the National Institute of Drug Abuse, by
`the Centers for Disease Control and Prevention, and
`by the Office of the Assistant Secretary for Health
`in the Department of Health and Human Services.
`The problem before us, as everybody in this
`audience knows, is an enormous one. We have
`enormous increase in the use of opioid analgesics,
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`about 20 percent, in the last decade or so. Opioid
`analgesic deaths have risen along with this.
`Prescription drug overdose deaths have increased
`about threefold since 1999. And ever since 2003,
`the number of overdose deaths from opioid
`analgesics have actually exceeded the number of
`such deaths from cocaine and heroin combined, a
`fact that I think a lot of people in the public
`don't fully appreciate. So we're really dealing
`with a huge problem here, and the question is: what
`can be done about it?
`You'll hear a lot about a number of efforts
`that have been taken on by people in the federal
`government and elsewhere to address the problem of
`prescription overdose deaths. But today our focus
`is simply on one of those things, and that is
`naloxone.
`As I think everybody in this room knows, and
`you will hear I'm sure in greater detail, naloxone
`is an opioid receptor antagonist, which is
`currently approved for use by injection only for
`the reversal of opioid depression, for the
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`diagnosis of opioid overdose, and for adjunct use
`in the treatment of septic shock.
`Currently, it's only being used by trained
`medical professionals, primarily in the emergency
`rooms and in ambulances. But the question before
`us is might there be potential new patient groups
`that might be brought. And, of course, there are a
`lot of important programs that are in place and a
`number of programs across the country that have
`pushed in this direction, including described in a
`recent MMWR article about which we're sure to hear.
`So the question is, what can be done to
`further the use of this product, if appropriate,
`among illicit drug users and for those who are on
`long-term narcotics, for example, those with
`chronic cancer pain.
`To put this in context, I just want to point
`to a couple of things. One is on the international
`level. I want to point to the UN Commission on
`Narcotic Drugs, which in 2012 released the
`following statement: the Commission "encourages all
`member states to include effective elements for the
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`prevention and treatment of drug overdose, in
`particular opioid overdose, in national drug
`policies where appropriate, and to share best
`practices and information on the prevention and
`treatment of drug overdose, in particular opioid
`overdose, including the use of opioid receptor
`antagonists such as naloxone," one of the longest
`sentences I think I've ever had to read.
`(Laughter.)
`DR. LURIE: Domestically, we have had
`parallel reaction, I think, and so I wanted to talk
`a little bit about the Office of National Drug
`Control Policy, ONDCP, colloquially known as the
`drug czar's office.
`The drug czar's office has its own
`prescription drug abuse plan, and that prescription
`drug abuse plan says -- and I'm quoting
`again -- that we should, "hold a public workshop to
`discuss medical and social issues related to
`naloxone use by nonmedical personnel," here we are,
`"and provide guidance to researchers, community
`groups, and the pharmaceutical industry on
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`potential routes to marketing approval for novel
`naloxone formulations." So in a lot of ways, this
`meeting is putting into effect something in the
`ONDCP plan.
`We had invited the ONDCP to come today, and
`unfortunately they were unable to. But in their
`stead, Gil Kerlikowske, who is the director of
`ONDCP, sent the following statement for me to read
`verbatim to you. And so here I go.
`"On behalf of the White House Office of
`National Drug Control Policy, I would like to
`welcome you to this important public workshop. In
`2010, the Obama administration's first drug
`strategy was released. This strategy, as well as
`subsequent strategies, recognizes the important
`role naloxone can play in overcoming drug
`overdoses.
`"With more people dying from unintentional
`drug overdoses than car accidents, it is vitally
`important that we do what is necessary to prevent
`drug abuse while also preventing drug overdoses and
`getting people the treatment they need.
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`"Thank you for taking time to discuss this
`issue, and I look forward to continuing this
`important conversation."
`So that's from Director Kerlikowske.
`So with that, what are our goals for this
`meeting? Well, the main purpose is to initiate a
`public discussion about whether naloxone should be
`made more widely available outside of conventional
`medical settings to reduce opioid overdose
`fatalities.
`We have a morning and an afternoon. The
`morning is really a scene setting kind of exercise.
`We'll discuss who's at risk for opioid overdose,
`what the epidemiology of overdose is. We'll
`describe attempts by public health groups to
`address overdoses in general. And then we'll talk
`about naloxone and its particular characteristics
`and how they affect the material that comes up
`really in the afternoon session. And we'll have a
`series of presentations that describe the
`experience of different groups using naloxone in
`nonmedical settings.
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`In the afternoon, we'll get to what, in a
`way, is the meat and potatoes of the meeting.
`We're going to talk about regulatory issues, what
`it would take to get an intranasal form of naloxone
`approved, what it would take to get a product
`switched from prescription to over-the-counter
`status. We'll have an industry perspective on why
`they might or might not want to enter the market,
`and we'll discuss the ethical issues that are
`involved in the studying of these products.
`Then we're going to have a very packed open
`public hearing, which we're looking forward to
`greatly. Twenty-eight people have signed up. And
`we're sorry for the short time that that affords
`everybody, but we also need everybody to be heard.
`So it's a very, very packed open public hearing
`session.
`After that, we'll have a final session on
`social and legal concerns, which will begin with
`lessons from other public health interventions,
`where the question of behavioral disinhibition, if
`you will, has been raised. And we'll hear about
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`the experience with the HPV vaccine, Gardasil. And
`then we'll have a panel discussion, which we look
`forward to being lively, in which all of these
`issues with be batted back and forth for all of our
`edification.
`I should say that the discussion with all of
`you in the audience is not confined to the open
`public hearing session. Each of the sessions that
`I've outlined has a time for question and answer.
`And I'll ask you to please identify yourself at the
`microphone, directly in the middle over here,
`before you speak at those question-and-answer
`sessions.
`Let me just mention a couple of logistical
`details before closing. As I've mentioned, we have
`a very full agenda, so we ask you to make it back
`in time so that we can cover everything in an
`expeditious way and so that I can get out of here
`to pick up my kids.
`(Laughter.)
`DR. LURIE: We do have ample breaks built
`in. Kiosks will be set up outside the meeting room
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`where refreshments will be sold during breaks and
`at lunch. There will be salads, sandwiches, other
`refreshments when we break for lunch. The
`bathrooms are out this door and to the right.
`Only those with FDA badges will be able to
`venture past this immediate area without going
`through security measures. In solidarity with you,
`I left my badge behind today so that I'm stuck here
`as well. As to logistics, we ask you to turn your
`cell phones off while you're in this room because
`signal transmission can interfere with the
`transcriber who is recording this meeting.
`So I wanted to, before closing, make sure to
`thank the people who are responsible for pulling
`this meeting together for us. And I know that many
`of you have dealt with them in person before coming
`here. Matt Petcovic and Jan Shelton were
`instrumental in pulling everything together. But
`more than anybody, I think, Mary Gross is the
`person who deserves a lot of credit for how well we
`believe this meeting is going to flow.
`So in conclusion, I just want to say that
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`this effort today is part of many things that the
`U.S. Government is doing about prescription drug
`abuse and about overdoses in particular. And this
`meeting will allow a discussion of various
`potential uses of naloxone.
`The purpose of the meeting is really twofold
`and bidirectional. One is for us to hear from you
`about the possibilities for naloxone by use outside
`of conventional medical settings as well as the
`potential risks, and for you to hear from us about
`the available regulatory pathways for naloxone.
`We want to show you what it would take for
`over-the-counter, what it would take to develop a
`intranasal form on the assumption that not
`everybody who has worked in the naloxone field may
`be as familiar with those rather intricate
`processes as might be the case. And we hope to
`show you, therefore, a roadmap to help us
`collectively make the best use of naloxone for the
`public health.
`Okay. That concludes my opening remarks.
`Doug, you're next.
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`Panel 1 – Moderator Bob Rappaport
`DR. RAPPAPORT: Good morning. I'm Bob
`Rappaport. I'm the director of the Division of
`Anesthesia, Analgesia and Addiction Products in the
`Center for Drug Evaluation and Research here at
`FDA. And I'm the moderator for the first panel
`today, and I'm pleased to see that there's so much
`interest in this important topic.
`The increasing numbers of unnecessary deaths
`due to opioid overdose in the U.S. is clearly a
`true public health crisis, and I know we're all
`here with the same agenda. And that is to
`establish whether allowing naloxone to become more
`widely available for use by nonmedical personnel in
`treating these overdoses is one mechanism that
`should be considered as a potential intervention.
`In order to make that assessment, it's
`important that we all start out on the same page in
`regard to what is actually known about naloxone and
`about the population that this drug would be
`administered to. And it's also important for us to
`acknowledge and understand the earlier and ongoing
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`public health strategies that have been employed to
`address this problem.
`To that end, we have three outstanding
`speakers for the first panel today. We'll begin
`with Dr. Len Paulozzi from CDC -- I'm sorry,
`Paulozzi. I do that to you every single time. I
`apologize -- who will provide us with data on the
`populations at risk for opioid overdose.
`Len will be followed by Mr. Nick Reuter from
`SAMHSA, who will tell us about other public health
`strategies that are addressing the opioid overdose
`problem. And last but certainly not least,
`Dr. Gregory Terman from the University of
`Washington will discuss the pharmacokinetics, the
`clinical benefits, and the potential toxicities of
`naloxone.
`We're on a very tight schedule today, as
`Dr. Lurie said, with a packed agenda. So each of
`the moderators, including myself, will be
`attempting to keep the speakers to their allotted
`times, and the question-and-answer session will be
`limited to 10 minutes. So I apologize if I have to
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`cut you off. We'll try to find time for questions,
`if possible, that weren't fitting into the allotted
`times.
`
`So let's begin, and I'm very pleased to
`introduce you to Dr. Paulozzi.
`Presentation – Len Paulozzi
`DR. PAULOZZI: Good morning, everyone. My
`job is to lay out some of the epidemiology of
`populations at risk from opioid overdose. I'm
`going to talk about the opioid analgesic
`epidemiology as well as heroin. And I'm going to
`cover some trends and then move on to risk factors.
`This is really why we're gathered here
`today, this figure which each year we add another
`year of data to this, and the numbers seem to keep
`going up. This shows data through 2009, national
`mortality data based on death certificates. We are
`up to about 15,000 deaths involving opioid
`analgesics in the United States with growing
`numbers in the last two or three years for heroin.
`As was already mentioned, for a number of
`years now, deaths involving opioid analgesics have
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`outnumbered deaths involving either heroin or
`cocaine in the United States.
`You can break down the opioid analgesic
`deaths into three subtypes by the available codes
`in the international classification of diseases.
`And there are basically these three groups shown
`here: the group of the codones, hydrocodone,
`oxycodone, morphine, codeine and so on, shown on
`the top line; methadone; and finally, the other
`synthetic narcotics, including fentanyl,
`merperidine, formerly propoxyphene, buprenorphine,
`et al.
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`I show this in part to emphasize the
`relative importance of these three groups, in
`particular methadone, where we are seeing some
`improvements and some flattening of the trends
`there. But methadone is really just 2 percent of
`all opioid analgesic prescriptions in the United
`States, yet it is involved in about one out of
`three opioid analgesic deaths in recent years.
`Moving on to risk factors, men are the
`largest risk group for opioid overdose in the
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`United States, whether, it's the analgesics or
`heroin. The analgesic bar is the center bar shown
`in orange. Heroin is in yellow. The male rate is
`twice that of the female, roughly, for the opioids
`and about four times greater among men for heroin.
`Age group, this is the group of all drug
`overdose death rates, so it's all drugs, not just
`opioids. And this slide is really just to
`demonstrate that if you look at the unintentional
`group in yellow or suicides involving drugs, or the
`group that is called "undetermined intent,"
`undetermined mostly whether it was a suicide or
`unintentional, the peak rates are in the 45 to 54
`year age group. So this really is mostly a
`middle-age problem.
`Rates really start to jump up in the 15 to
`19 age group, particularly at age 18 is when kids
`leave the home, go off to college, and we see the
`largest increase when you look at it by single
`years of age. There's something of a bulge growing
`now in the people in their 20s, and after age 60,
`rates drop off dramatically. When you get into
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`ages 65 plus, whether it's -- including suicides,
`the rates are relatively low compared to people in
`their 40s.
`This is the same thing: rates by age group.
`But here I'm looking at drug overdose death rates
`by drug type. And basically, you see the same kind
`of pyramid, whether you're looking at cocaine or
`methadone or other opioids. The only real
`difference there is the heroin bar in yellow where
`the peak age is 25 to 34 years of age. For the
`other age groups, 45 to 54 remains the peak age in
`terms of rates.
`I show this slide really just to contrast it
`with the overdose curve by age group. These are
`opioid prescriptions per person by age group in the
`U.S. in 2009 -- this is data that was published in
`JAMA from Dr. Volkow of NIDA -- and really looked
`at this way, people over age 60 get more
`prescriptions per person than people in middle age.
`So it's in contrast to, the peak in middle age,
`it's really not a similar pattern in terms of usage
`measured this way.
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`Rounding out the demographic variables, this
`is race, ethnicity data from 2008 in the United
`States, again, cocaine, opioid analgesics, and
`heroin. For the opioid analgesics, the highest
`rates are in non-Hispanic whites closely followed
`by American Indians and Alaska natives. Hispanic
`whites, blacks, Asian Pacific Islanders are much
`lower. For heroin shown in yellow, the non-
`Hispanic whites still have the highest rates with
`Hispanic and blacks being slightly lower; American
`Indians also having rates comparable to Hispanics
`and blacks.
`This is an attempt to look at urbanization
`by drug type. So in order to do this in what I
`thought was the fairest fashion, I just looked at
`states that have centralized medical examiner
`systems because the degree of specification of
`drugs on death certificates seems to vary a lot
`between coroner and medical examiner systems.
`So if you look at these 16 states and you
`restrict it just to U.S. whites, which that
`restriction is because of the confounding between
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`race and urban residence, you can see that the
`highest rates for drug overdose deaths are in
`non-core, non-metro, the most rural counties over
`the right side of the figure, for opioid
`analgesics. It's not a stair step phenomenon, but,
`in general, the non-metropolitan counties have
`higher rates for opioid analgesics. In contrast,
`the heroin rates are significantly higher in large,
`central, metro counties and get progressively lower
`as you proceed to non-metropolitan counties.
`This slide does two things. It shows that
`the drug overdose death rates in 2008 are
`concentrated in Appalachian states, Florida,
`Louisiana, states in the southwest. I borrowed
`this figure from a recent MMWR article, which
`focused on naloxone prevention programs in 2010 in
`the United States, some of the authors of which are
`here today. And I do this to emphasize the
`contrast between the location of the current
`programs and the drug overdose mortality rates.
`These are drug overdose deaths. See, these
`are all drugs, but the bulk of them are going to be
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`related to either heroin or opioid analgesics. And
`this is maybe related to the rural nature of the
`states, maybe related to income factors. It's
`unclear as to why we have these geographic
`patterns.
`Moving on to other personal characteristics
`of people who die of drug overdoses, a lot of this
`information has to come from sources other than
`death certificates. So you'll see me citing
`frequently studies based on state medical examiner
`data. And this is a study we did a few years ago
`looking at unintentional pharmaceutical overdose
`deaths in West Virginia in one year, 295 some
`deaths, using medical examiner records.
`We found that about 80 percent of the people
`had some history of substance abuse, whether
`alcohol or drugs. Forty-three percent had some
`other kind of mental illness, other meaning not
`substance abuse. And about one out of five people
`used a nonmedical route of administration, meaning
`that they injected the drugs or ground up the drugs
`and snorted them. And about one in six people had
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`a history of a previous overdose.
`Another study done later in 2008-2009 in
`Utah, a very different setting from West Virginia,
`but they found that about 60 percent of people had
`a history of substance abuse, about half had what
`they called signs of nonmedical use, which in this
`case was defined as use without a prescription or
`using nonmedical routes of administration.
`Most people had a history of some kind of
`chronic pain. And, again, most people had some
`kind of mental illness other than substance abuse
`diagnosed by a provider, was the definition that
`they used in that study.
`So those medical examiner studies typically
`are numerator data. They don't have comparisons.
`You're just looking at people who died, so you
`don't have the ability to see whether it's really a
`risk factor. There are a few studies, however,
`that do have some comparison groups.
`In West Virginia, actually, we were able to
`compare the people who died or look at the rates by
`residence in counties based on their poverty level
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`to basically look to see whether counties that had
`higher percentages under the poverty level had
`higher rates. And residents in counties with 22 to
`39 percent of the population living in poverty,
`which was the highest poverty level, had a
`relatively high risk of 2.1 compared to residents
`in a West Virginia county with the lowest level of
`poverty, 9 to 16 percent.
`Also, related to income is Medicaid
`eligibility. In Washington state,
`Medicaid-enrolled Washington residents were studied
`compared to non-Medicaid-enrolled Washington
`residents. The Medicaid group had almost six times
`a risk of a fatal prescription opioid overdose in
`that study.
`Similarly, there are some studies that are
`able to generate relative risks or hazard ratios,
`and I have combined some of them here looking at
`substance abuse and mental health problems.
`A study of group health by Dunn in 2010
`showed a substance abuse diagnosis in patients on
`chronic opioid therapy had 2.6 relative risk.
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`These are developed by just combining the rates in
`the study. They did not do the statistical
`testing.
`Another study by Bohnert in 2011 saw that a
`substance abuse disorder among chronic pain
`patients was associated with a risk of opioid
`overdose, a significant relative risk of 2.5.
`Depression diagnosis, again in patients on
`chronic opioid therapy in the group health study,
`was associated with a a threefold increase in risk.
`And psychiatric disorders other than substance
`abuse in the Bohnert VA study had a relative risk
`of 1.9, which was statistically significant.
`Finishing up these other personal
`characteristics, lack of a prescription for the
`involved drugs among overdose deaths has been a
`common feature of a number of state studies. In
`West Virginia, 63 percent did not have a
`prescription in the state prescription drug
`monitoring program for one or more of the
`pharmaceuticals involved in their deaths. In Ohio,
`25 percent did not have a prescription in the
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`previous three years in the state prescription
`monitoring program. In Utah, unintentional opioid
`deaths, 37 percent, again based on the state
`prescription monitoring program.
`If you look particularly at methadone in a
`couple of the states, North Carolina and Ohio,
`about three-quarters of the people did not have a
`prescription in their state prescription monitoring
`programs for the methadone that was involved in
`their deaths.
`And lastly, prescription history, there have
`been a few studies in recent years looking at
`prescription history of individuals oftentimes
`using state prescription monitoring program data.
`Again, the Ohio study found that one out of six
`people who died of a prescription overdose had
`filled prescriptions from an average of five
`prescribers per year over the previous three years.
`In the study we did in West Virginia, it was
`similar, about 21 percent had filled prescriptions
`from five or more prescribers in the preceding
`year.
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`In a study we did more recently in the state
`of New Mexico, these are crude odds ratios, just to
`show that as the mean number of prescribers goes
`up -- and multiple prescribers is what people often
`use as the definition of, "doctor shopping." there
`was a fairly steady increase in risk. And when you
`get into people with 10, 15 or 20 or 30, you're
`approaching 10 times the odds ratio or 10 times the
`risk of dying of a drug overdose.
`This is from the same study. It looks at
`prescriptions rather than numbers of prescribers,
`so multiple prescriptions for controlled substances
`of any kind. Again, associated risk of
`unintentional drug overdose in New Mexico. And
`when you get into numbers like 30 to 35
`prescriptions, the odds ratios are 68 for people in
`that category.
`As a last measure, in a growing number of
`studies about dosage, daily dosage usually
`converted to morphine equivalence as a daily
`dosage, measured in different ways and different
`cut points. The first study probably was the study
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`by Dunn looking at people with chronic pain in the
`Group Health Cooperative. They looked at people
`with more than 100, a 100 or more morphine
`milligram equivalence per day daily dosage,
`compared them to people with no recent use of
`opioids and found a relative risk of 8.8.
`Braden looked at people with a dose of over
`120 compared to people below the median dose, found
`a small increase in risk, although it was
`statistically significant of 1.08.
`The Bohnert VA study, similarly, over 100,
`was associated with a relative risk of 7. And
`Gomes' study in Canada, dosage over 400, elevated
`risk, and our study in New Mexico, dosage over 120
`compared with less than 1
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