FOOD AND DRUG ADMINISTRATION
1
CENTER FOR DRUG EVALUATION AND RESEARCH
2 3 4 5 6 PSYCHOPHARMACOLOGIC DRUGS 7 ADVISORY COMMITTEE 8 9 10 11 THURSDAY, MARCH 21, 2013 12 8:00 a.m. to 5:10 p.m. 13 14 15 16 17 18
FDA White Oak Campus
19
Building 31, The Great Room (Room 1503)
20
White Oak Conference Center
21
Silver Spring, Maryland
Meeting Roster 1
ACTING DESIGNATED FEDERAL OFFICER (Non-Voting) 2
Minh Doan, PharmD 3
Division of Advisory Committee & Consultant
4
Management
5
Office of Executive Programs, CDER, FDA
6
7
PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE 8
MEMBERS (Voting) 9
Victor De Gruttola, ScD 10
Professor and Chair of Biostatistics
11
Department of Biostatistics
12
Harvard School of Public Health
13 Boston, MA 14 15 Michael Y. Hwang, MD 16
Adjunct Professor of Psychiatry
17
New York Medical College
18 Montrose, NY 19 20 21 22
Christopher J. Kratochvil, MD 1
Associate Vice Chancellor for Clinical
2
Research
3
Professor of Psychiatry & Pediatrics
4
University of Nebraska Medical Center
5
Omaha, NE
6
7
Elizabeth McCarthy, MA, LPC 8
(Consumer Representative) 9
Psychotherapist
10
Horizon Counseling Services
11
Royal Oak, MI
12
13
ACTING INDUSTRY REPRESENTATIVE TO THE COMMITTEE 14
(Non-Voting) 15
Richard L. Leff, MD 16
(Acting Industry Representative) 17
Independent Pharmaceutical Industry Consultant
18 Chadds Ford, PA 19 20 21 22
TEMPORARY MEMBERS (Voting) 1
Louis E. Baxter, Sr., MD, FASAM 2
Executive Medical Director
3
Professional Assistance Program of
4
New Jersey, Inc.
5 Princeton, NJ 6 7 Vernon M. Chinchilli, PhD 8
Distinguished Professor and Chair
9
Department of Public Health Sciences
10
The Pennsylvania State University College of
11 Medicine 12 Hershey, PA 13 14 Edward C. Covington, MD 15 (Acting Chairperson) 16
Director, Neurological Center for Pain
17
Neurological Institute
18
Cleveland Clinic Foundation
19
Cleveland, OH
20
21
Eve Espey, MD, MPH 1
Professor
2
Department of Obstetrics and Gynecology
3 Albuquerque, NM 4 5 Adam J. Gordon, MD, MPH 6
Associate Professor of Medicine and
7
Advisory Dean
8
University of Pittsburgh School of Medicine
9 Pittsburgh, PA 10 11 Geri Hewitt, MD 12 Associate Professor 13
Department of Obstetrics and Gynecology
14
The Ohio State University
15 Columbus, OH 16 17 Judith M. Kramer, MD, MS 18 Professor of Medicine 19
Duke University Medical Center
20
Durham, NC
21
Laura F. McNicholas, MD, PhD 1
Clinical Associate Professor of Psychiatry
2
Center for Studies of Addiction
3
University of Pennsylvania School of
4 Medicine 5 Philadelphia, PA 6 7 Robert Steinbrook, MD 8
Professor Adjunct of Internal Medicine
9
Yale School of Medicine
10
New Haven, CT
11
12
Michael L. Yesenko, MDiv 13 (Patient Representative) 14 Brookville, MD 15 16 Daniel Zelterman, PhD 17 Professor 18
Division of Biostatistics, Epidemiology and
19
Public Health
20
Yale University School of Medicine
21
New Haven, CT
FDA PARTICIPANTS (Non-Voting) 1 Bob A. Rappaport, MD 2 Director 3
Division of Anesthesia, Analgesia, and
4
Addiction Products (DAAAP)
5
Office of Drug Evaluation II (ODEII)
6 CDER, FDA 7 8 Celia Winchell, MD 9
Clinical Team Leader
10
DAAAP, ODEII, CDER, FDA
11 12 Rigoberto Roca, MD 13 Deputy Director 14
DAAAP, ODEII, CDER, FDA
15 16 17 18 19 20 21 22
C O N T E N T S
1
AGENDA ITEM PAGE
2
Call to Order and Introduction of Committee
3
Edward Covington, MD 10
4
Conflict of Interest Statement
5
Minh Doan, PharmD 14
6
FDA Introductory Remarks
7
Celia Winchell, MD 17
8
Sponsor Presentations – Titan Pharmaceuticals 9
Introduction
10
Marc Rubin, MD 24
11
Background and Medical Need
12
Andrea Barthwell, MD, FASAM 31
13 Clinical Efficacy 14 Kate Glassman-Beebe, PhD 41 15 Clinical Safety 16 Steve Chavoustie, MD 61 17
Risk Evaluation and Mitigation Strategy (REMS)
18 Garry Neil, MD 74 19 Conclusion 20 Kate Glassman-Beebe, PhD 84 21 Clarifying Questions 87 22
C O N T E N T S (continued)
1
AGENDA ITEM PAGE
2
FDA Presentations 3
Review of Probuphine Clinical Data
4
Efficacy and Safety
5 Rachel Skeete, MD 135 6 David Petullo, MS 153 7 Rachel Skeete, MD 164 8
Contraceptive Implants: Regulatory History and
9 Lessons Learned 10 Barbara Wesley, MD, MPH 187 11 Clarifying Questions 200 12
FDA Presentations (continued) 13
Risk Evaluation and Mitigation Strategy for
14
Probuphine
15
Jason Bunting, PharmD 213
16
Clarifying Questions 234
17
Open Public Hearing 245
18
Charge to the Committee
19
Celia Winchell, MD 291
20
Questions to the Committee and Discussion 293
21
Adjournment 416
P R O C E E D I N G S 1 (8:00 a.m.) 2 Call to Order 3 Introduction of Committee 4
DR. COVINGTON: Good morning, everyone. I'd
5
like to start off by asking everyone to please
6
silence your cell phones, and I'll start with mine,
7
should I forget, and any other devices that you
8
have. And I'd like to identify the FDA press
9
contact, Morgan Liscinsky. If you would please
10
stand up and let people know who you are. Thank
11
you.
12
I'd like to ask all the members,
13
consultants, the FDA panel, and the DFO to please
14
state your name into the record and your
15
affiliation. Dr. Kramer?
16
DR. KRAMER: Judith Kramer, professor of
17
medicine at Duke University. I have a background
18
in pharmacy, general internal medicine, and
19
clinical research for the last 27 years.
20
DR. STEINBROOK: Robert Steinbrook, Yale
21
School of Medicine.
MR. YESENKO: Michael Yesenko, patient
1
representative.
2
DR. MCNICHOLAS: Laura McNicholas,
3
University of Pennsylvania and the Philadelphia VA.
4
DR. BAXTER: I'm Dr. Louis E. Baxter, Sr.,
5
executive medical director, Professional Assistance
6
Program of New Jersey.
7
DR. GORDON: Adam Gordon, internal medicine,
8
addiction medicine, and health services
9
investigator for the University of Pittsburgh.
10
MS. MCCARTHY: Liz McCarthy. I'm a
11
psychotherapist, Royal Oak, Michigan.
12
DR. COVINGTON: I'm Ed Covington. I'm the
13
director of the Neurologic Center for Pain at
14
Cleveland Clinic.
15
DR. DOAN: Minh Doan, acting designated
16
federal officer.
17
DR. KRATOCHVIL: I'm Chris Kratochvil. I'm
18
the associate vice chancellor for clinical research
19
at the University of Nebraska Medical Center.
20
DR. HWANG: Michael Hwang, New York Medical
21
College and FDR VA in New York.
DR. ZELTERMAN: Dan Zelterman, professor of
1
biostatistics at Yale.
2
DR. CHINCHILLI: Vern Chinchilli. I'm a
3
biostatistician at Penn State, Hershey.
4
DR. ESPEY: Eve Espey, professor of
5
obstetrics and gynecology at the University of New
6
Mexico.
7
DR. HEWITT: Geri Hewitt, associate
8
professor of obstetrics and gynecology and
9
pediatrics at Ohio State.
10
DR. WINCHELL: Celia Winchell. I'm the
11
medical team leader for addiction drug products in
12
the Division of Anesthesia, Analgesia, and
13
Addiction Products in the Center for Drug
14
Evaluation and Research at FDA.
15
DR. ROCA: I'm Rigo Roca. I'm deputy
16
division director.
17
DR. RAPPAPORT: I'm Bob Rappaport, the
18
division director.
19
DR. COVINGTON: Dr. Leff, could you
20
introduce yourself?
21
DR. LEFF: Yes. I'm Dr. Richard Leff. I'm
the industry representative, and I'm an independent
1
consultant.
2
DR. DEGRUTTOLA: Victor DeGruttola,
3
statistician, Harvard School of Public Health.
4
DR. COVINGTON: All right. For topics such
5
as those being discussed at today's meeting, there
6
are often a variety of opinions, some of which are
7
quite strongly held. Our goal is that today's
8
meeting will be a fair and open forum for
9
discussion of these issues, and that individuals
10
can express their views without interruption.
11
Thus, as a gentle reminder, individuals will be
12
allowed to speak into the record only if recognized
13
by the chair. And we look forward to a productive
14
meeting.
15
In the spirit of the Federal Advisory
16
Committee Act and the Government in the Sunshine
17
Act, we ask that the advisory committee members
18
take care that their conversations about the topic
19
at hand take place in the open forum of the
20
meeting. We are aware that members of the media
21
are anxious to speak with the FDA about these
proceedings. However, FDA will refrain from
1
discussing the details of this meeting with the
2
media until its conclusion.
3
Also, the committee is reminded to please
4
refrain from discussing the meeting topic during
5
breaks or at lunch. And thank you for that.
6
I'll pass it to Minh Doan.
7
Conflict of Interest Statement 8
DR. DOAN: The Food and Drug Administration
9
is convening today's meeting of the
10
Psychopharmacologic Drugs Advisory Committee under
11
the authority of the Federal Advisory Committee Act
12
of 1972. With the exception of the industry
13
representative, all members and temporary voting
14
members of the committee are special government
15
employees or regular federal employees from other
16
agencies and are subject to federal conflict of
17
interest laws and regulations.
18
The following information on the status of
19
this committee's compliance with federal ethics and
20
conflict of interest laws covered by, but not
21
limited to, those found at 18 USC Section 208 is
being provided to participants in today's meeting
1
and to the public.
2
FDA has determined that members and
3
temporary voting members of the committee are in
4
compliance with federal ethics and conflict of
5
interest laws. Under 18 USC Section 208, Congress
6
has authorized FDA to grant waivers to special
7
government employees and regular federal employees
8
who have potential financial conflicts when it is
9
determined that the agency's need for a particular
10
individual's services outweighs his or her
11
potential financial conflict of interest.
12
Related to the discussion of today's
13
meeting, members and temporary voting members of
14
this committee have been screened for potential
15
financial conflicts of their own as well as those
16
imputed to them, including those of their spouses
17
or minor children and, for purposes of 18 USC
18
Section 208, their employers. These interests may
19
include investments, consulting, expert witness
20
testimony, contracts, grants, CRADAs, teaching,
21
speaking, writing, patents and royalties, and
primary employment.
1
Today's agenda involves the discussion of
2
new drug application 204442, Probuphine,
3
buprenorphine hydrochloride and ethylene vinyl
4
acetate, subdermal implant, submitted by Titan
5
Pharmaceuticals, Inc., and its safety and efficacy
6
for the proposed indication for maintenance
7
treatment of opioid dependence.
8
This is a particular matters meeting, during
9
which specific matters related to Titan
10
Pharmaceuticals' NDA will be discussed. Based on
11
the agenda for today's meeting and all financial
12
interests reported by the committee members and
13
temporary voting members, no conflict of interest
14
waivers have been issued in connection with this
15
meeting.
16
To ensure transparency, we encourage all
17
standing members and temporary voting members to
18
disclose any public statements that they may have
19
made concerning the products at issue.
20
With respect to FDA's invited industry
21
representative, we would like to disclose that
Dr. Richard Leff is serving as a nonvoting industry
1
representative, acting on behalf of regulated
2
industry. Dr. Leff's role at this meeting is to
3
represent industry in general and not any
4
particular company. Dr. Leff is an independent
5
pharmaceutical consultant.
6
We would like to remind members and
7
temporary voting members that if the discussions
8
involve any other products or firms not already on
9
the agenda for which an FDA participant has a
10
personal or imputed financial interest, the
11
participants need to exclude themselves from such
12
involvement, and their exclusion will be noted for
13
the record.
14
FDA encourages all other participants to
15
advise the committee of any financial relationships
16
that they may have with the firms at issue. Thank
17
you.
18
DR. COVINGTON: Dr. Celia Winchell has
19
introductory remarks.
20
FDA Introductory Remarks 21
DR. WINCHELL: Good morning. Dr. Covington,
members of the Psychopharmacologic Drugs Advisory
1
Committee, and invited guests, thank you for your
2
participation in this important meeting. Today we
3
will ask for your assistance in our evaluation of
4
Titan's application to market Probuphine, an
5
implantable formulation of buprenorphine, as a
6
treatment for opioid dependence.
7
Buprenorphine was initially approved in 1981
8
as an injectable analgesic. It is a partial
9
agonist at the mu receptor, unlike most opioid
10
analgesics, which are full agonists. Agonist
11
maintenance therapy of opioid dependence is a
well-12
established paradigm. In the several decades since
13
methadone maintenance treatment was introduced,
14
epidemiologic studies have established that
15
participation in methadone treatment reduces
16
mortality and HIV seroconversion.
17
However, to control the risks of diversion
18
and accidental overdose, methadone treatment is
19
limited by law to specially registered opioid
20
treatment programs, or OTPs. Patients must report
21
to the OTP daily for supervised administration of
their medication until they're sufficiently stable
1
to begin to earn take-home doses, according to a
2
specific schedule.
3
Buprenorphine was developed as a treatment
4
for opioid dependence because some of its
5
pharmacologic properties suggested it could serve
6
as a safer alternative to methadone that would also
7
be less attractive for diversion and abuse, and as
8
such, could be made available in physicians'
9
offices rather than being limited to supervised
10
dosing in the OTP setting.
11
Unfortunately, in the decade since the
12
introduction of sublingual buprenorphine for the
13
treatment of opioid dependence, buprenorphine
14
sublingual products have been increasingly
15
identified in the illicit drug market, and it's
16
known that they are diverted, abused, and misused.
17
Additionally, they've been implicated in an
18
increasing number of cases of accidental poisonings
19
of small children.
20
Therefore, a depot injection or an
21
implantable product, which would be difficult to
divert or abuse and would be less likely to be
1
accidentally ingested by small children, offers
2
potential advantages.
3
In addition, patients on sublingual
4
buprenorphine periodically discontinue use of their
5
medication in order to allow its blockade
6
of exogenous opioids to dissipate so they can
7
experience the effects of their opioid of choice,
8
and with a depot or implantable, this would not be
9
possible. Probuphine was developed to provide
10
these types of advantages.
11
The division agrees with Titan, that an
12
implantable formulation of buprenorphine has the
13
potential to meet an important public health need.
14
We also agree with Titan that the studies show that
15
Probuphine-treated patients provide opioid-negative
16
urine samples more frequently than placebo-treated
17
patients. However, upon review, we've concluded
18
that the distribution of results is disappointing.
19
We will ask you to discuss whether you think
20
the product's efficacy is clinically significant.
21
Have the patients modified their drug use behavior
enough to benefit?
1
In addition to the benefits to the patient,
2
there are potential public health benefits to a
3
product that would be less likely to be diverted or
4
abused and less likely to come into accidental
5
contact with others in the patients' households,
6
particularly children.
7
However, it appears that many of the
8
patients treated with Probuphine may require
9
supplemental sublingual buprenorphine sporadically
10
throughout the treatment period. If patients
11
treated with Probuphine still have a supply of
12
sublingual buprenorphine in the home, does the
13
product provide the purported benefit with respect
14
to diversion, abuse, and accidental pediatric
15
exposure?
16
From a safety standpoint, fewer than 300
17
patients have been treated with this product, and
18
most of them had only one six-month cycle in what
19
could be potentially a lifelong treatment.
20
We did not identify systemic risks that
21
differ from the currently available sublingual
buprenorphine products, but we do have concerns
1
about the risks associated with the implantation
2
and removal procedures and the potential
3
complications such as device migration, expulsion,
4
and extrusion.
5
We're aware of these types of complications
6
associated with Norplant, a product that's similar
7
in format and in the procedures necessary for
8
implantation and removal. Even though the Norplant
9
procedures were performed by surgically trained
10
physicians, surgical training is not common among
11
physicians currently involved in providing
12
buprenorphine treatment of addiction.
13
Although serious procedural complications
14
were not observed in the clinical trials with
15
Probuphine, the database may simply be too small to
16
rule out these types of events. We'll ask you to
17
discuss whether the safety database is large enough
18
to characterize the risks.
19
Titan is proposing a closed distribution
20
system to ensure that every health care provider
21
performing the implantation and removal procedures
has undergone a hands-on training session.
1
However, we know that very few physicians with
2
surgical training are currently prescribing
3
sublingual buprenorphine.
4
We'll ask you to discuss how a surgical
5
procedure could fit into the current setting of
6
addiction treatment and whether the risk evaluation
7
and mitigation strategy proposed by Titan can
8
realistically be implemented within an addiction
9
treatment practice and is sufficient to mitigate
10
the risk of complications.
11
Your deliberations and recommendations will
12
play an important role in our decision-making
13
process. I would like to thank you for taking time
14
from your other extensive responsibilities to
15
participate in this meeting. Thank you.
16
DR. COVINGTON: Thank you.
17
Both the FDA and the public believe in a
18
transparent process for information gathering and
19
decision making. To ensure such transparency at
20
the advisory committee meeting, FDA believes that
21
it is important to understand the context of an
individual's presentation.
1
For this reason, FDA encourages all
2
participants, including the sponsor's non-employee
3
presenters, to advise the committee of any
4
financial relationships that they may have with the
5
firm at issue, such as consulting fees, travel
6
expenses, honoraria, and interests in the sponsor,
7
including equity interests and those based on the
8
outcome of the meeting.
9
Likewise, FDA encourages you at the
10
beginning of your presentation to advise the
11
committee if you do not have any such financial
12
relationships. If you choose not to address this
13
issue of financial relationships at the beginning
14
of your presentation, it will not preclude you from
15
speaking.
16
We'll now proceed with Titan's
17
presentations, beginning with Dr. Marc Rubin.
18
Sponsor Presentation – Marc Rubin 19
DR. RUBIN: Mr. Chairman, members of the
20
committee, and members of the Food and Drug
21
Administration, good morning. My name is Marc
Rubin, and I am the executive chairman of Titan
1
Pharmaceuticals.
2
Today we are here to present data and
3
address your questions on Probuphine, which is
4
intended for the maintenance treatment of opioid
5
dependence. Opioid dependence is a chronic,
6
relapsing, potentially fatal neurobiological
7
disease, and importantly, opioid dependence impacts
8
not only the person with the disease, but also has
9
an enormous overall impact on the family and on
10
society.
11
It is now accepted by the medical community
12
as a medical diagnosis, with an understanding that
13
many patients can be treated successfully with
14
medication-assisted therapy.
15
Unfortunately, while medical treatments for
16
dependence have benefitted many people, some of the
17
treatments themselves, including buprenorphine,
18
have contributed to the public health crisis
19
through abuse, misuse, and diversion, and
20
increasingly observed accidental pediatric
21
injection. These factors combine to make opioid
dependence one of the most challenging and one of
1
the most complex conditions to manage in clinical
2
practice.
3
Buprenorphine is currently the preferred
4
maintenance treatment for many opioid-dependent
5
patients in the United States. In contrast to
6
methadone, sublingual buprenorphine is used in a
7
medical office space setting, which has
8
substantially improved patient access to therapy.
9
It is available as tablets for sublingual
10
administration or as a sublingual film, and is
11
inherently less reinforcing than older
12
pharmacotherapies like methadone. However, there
13
is still room for improvement.
14
A recent draft guidance on abuse-deterrent
15
opioids issued by the FDA in January underscores
16
the significance of the U.S. prescription opioid
17
abuse problem. This guidance emphasizes the need
18
for abuse-deterrent formulations, which include
19
delivery systems, and specifically points to
20
subcutaneous implants as a way to discourage direct
21
patient access to opioids and to minimize risk.
We developed Probuphine to provide a
1
treatment alternative for the management of opioid
2
dependence, and it is indicated to be used in
3
conjunction with patient counseling.
4
Probuphine is a subdermally implanted,
5
sustained-release formulation of the FDA-approved
6
drug buprenorphine, and it's formulated by blending
7
buprenorphine hydrochloride and ethylene vinyl
8
acetate, or EVA, into a solid matrix impact. And
9
you may be familiar with EVA, as it is a major
10
component in other implantable products used
11
therapeutically in contraception, vascular surgery,
12
and ocular disease. There is no reservoir in the
13
matrix formulation, so there is no risk of drug
14
dumping.
15
Following subdermal insertion, buprenorphine
16
is released through dissolution, followed by tissue
17
absorption that provides stable, non-fluctuating
18
plasma buprenorphine concentrations over the
19
six-month treatment period.
20
The implants are inserted under local
21
anesthesia during a simple office-based procedure
that takes about 10 to 15 minutes. At the end of
1
six months of treatment or at any time treatment
2
needs to be discontinued, the implants can be
3
removed in a similar office procedure and a new set
4
of implants can be inserted if medically indicated.
5
Our goal in developing Probuphine was to
6
provide an alternative delivery form of
7
buprenorphine that is safe and effective for the
8
treatment of opioid-dependent patients and,
9
importantly, that reduces the public health risks
10
associated with many current medication-assistance
11
treatment regimens.
12
Probuphine was designed to deliver
13
buprenorphine treatment without interruption in
14
a way that eliminates the classic model of
15
prescribing and dispensing directly to the patient,
16
thus eliminating direct patient access prior to
17
implantation and its attendant risks of abuse,
18
diversion, and accidental pediatric exposure.
19
Prior to beginning the studies, it was
20
agreed with the FDA that the major metric of
21
efficacy would be a decrease in opioid abuse, and
as will be presented, we achieved both
1
statistically significant and clinically meaningful
2
results.
3
The FDA has outlined four key areas for
4
discussion at today's advisory committee meeting.
5
During the remainder of the presentation, we'll
6
provide data and describe our proposed commitments
7
to address each of the four discussion points.
8
We'll present phase 3 data results from two
9
placebo-controlled studies that show Probuphine is
10
efficacious for the maintenance treatment of opioid
11
dependence at the proposed dose of four to five
12
implants.
13
We'll review phase 3 safety data that
14
demonstrate Probuphine's systemic safety is
15
comparable to that of approved buprenorphine
16
formulations for the treatment of opioid
17
dependence, and that the implant-related safety
18
profile is consistent with those of other approved
19
implantable medications.
20
We will summarize our proposed risk
21
evaluation and mitigation strategy, or REMS, that
includes comprehensive training for implant
1
procedures and describes controls on the
2
prescribing, ordering, and shipping of Probuphine.
3
And we'll review information related to the safety
4
of the implant components.
5
Our speakers today include Dr. Andrea
6
Barthwell, who will review the scope of opioid
7
abuse and the need for new treatments;
8
Dr. Katherine Glassman-Beebe, who will present
9
the efficacy and pharmacokinetic data from our
10
clinical study program; Dr. Steve Chavoustie, who
11
will summarize the clinical safety data; and
12
Dr. Garry Neil of Braeburn Pharmaceuticals, which
13
has licensed the rights to Probuphine, who will
14
describe the proposed risk evaluation and
15
mitigation strategy, or REMS; and then finally,
16
Dr. Glassman-Beebe, who will return to close our
17
presentation.
18
We have with us additional experts who may
19
assist us in answering questions from the
20
committee. The outside presenters and these
21
experts have been compensated for their time, but
none own stock in Titan Pharmaceuticals.
1
Thank you, and I will now turn the
2
presentation over to Dr. Barthwell.
3
Sponsor Presentation – Andrea Barthwell 4
DR. BARTHWELL: Thank you, Dr. Rubin.
5
Good morning, Mr. Chairman and committee.
6
I'm Andrea Barthwell, a diplomate in the American
7
Board of Addiction Medicine. Between 2002 and
8
2004, I served in the Office of National Drug
9
Control Policy as the principal advisor in the
10
administration on issues of demand reduction. I'm
11
also the founder and CEO of the treatment program
12
Two Dreams, with locations in Chicago and the Outer
13
Banks of North Carolina.
14
I've treated opioid dependence since 1985,
15
and served as the executive secretary of the Center
16
for Substance Abuse Treatment office-based opioid
17
treatment consensus document. Today, I treat
18
patients on buprenorphine and see the benefits in
19
the real-world setting.
20
To provide some perspective on opioid
21
dependence in the United States and the unmet
medical needs related to the treatment of opioid
1
dependence, I'll discuss opioid misuse, abuse,
2
diversion, and overdose; review goals and
3
challenges of medication-assisted treatment with
4
buprenorphine; and describe the appropriate
5
patients for Probuphine.
6
Opioid abuse and dependence are not limited
7
to illegal drugs like heroin. Non-medical use of
8
prescription opioids has evolved into a major
9
public health problem in the United States. As
10
federal and state regulations have begun to address
11
the non-medical use of prescription opioids, heroin
12
use is increasing.
13
According to the National Survey on Drug Use
14
and Health, it is estimated that four and a half
15
million people are current non-medical users of
16
prescription opioids, while an additional 620,000
17
use heroin. Approximately 1.8 million of these are
18
dependent on prescription opioids, and 369,000 on
19
heroin. Fewer than half of the people addicted to
20
prescription opioids sought any treatment in 2011.
21
While drug use is a preventable behavior,
NIDA scientists have characterized the chronic,
1
potentially fatal disease of chemical dependency as
2
a primary disease of brain reward, motivation,
3
memory, and related circuitry. Dysfunction in
4
these circuits leads to characteristic
5
biopsychosocial changes. This is reflected in an
6
individual pathologically pursuing reward and
7
relief by substance use without regard for
8
consequences. This results in loss of mental
9
peace, physical well-being, and personal
10
productivity.
11
The chronic disease of opioid dependence is
12
physical dependence on and a subjective need, such
13
as craving, for opioid drugs. As with other
14
chronic and relapsing disorders, the goal is to
15
make positive, incremental changes.
16
Decades of study support the view that
17
opioid dependence is a potentially fatal disease.
18
Individuals diagnosed with opioid dependence are at
19
increased risk of death. Currently, the principal
20
causes are HIV/AIDS, suicide, overdose, infection,
21
and trauma. But this disease can be treated with
medication-assisted treatment.
1
Medication-assisted treatment, or MAT,
2
includes medication approved by the U.S. Food and
3
Drug Administration for detoxification or
4
maintenance treatment. Currently available
5
medications include methadone, buprenorphine,
6
buprenorphine/naloxone combination, and naltrexone.
7
In 2000, the Drug Abuse Treatment Act, or
8
DATA 2000, allowed practitioners who meet certain
9
qualifying criteria to dispense or prescribe
10
Schedule III to V controlled substances. MAT can
11
be provided in an opioid treatment program, defined
12
as any treatment program certified by SAMHSA, or in
13
a physician's office.
14
Continuous and uninterrupted MAT reduces
15
high-risk behavior, crime, drug use, leading to
16
improved health outcomes and improved psychosocial
17
functioning. It is important to note that even a
18
few weeks of abstinence in this patient population
19
improves overall outcomes and is a significant goal
20
of medication-assisted treatment. I've seen these
21
improvements in my practice firsthand.
Additionally, studies have shown that
1
reduction in use highly correlates with retention
2
in treatment. For those who are retained, the risk
3
of death is reduced by 75 percent.
4
The usual buprenorphine treatment paradigm
5
for opioid dependence comprises three phases.
6
During the induction phase, the initial goal is to
7
eliminate opioid withdrawal symptoms and to achieve
8
steady-state medication blood levels between
9
dosing. Dosing is closely supervised.
10
During the stabilization phase, the goal is
11
to eliminate withdrawal and craving and to
12
extinguish drug using and seeking. And during the
13
maintenance phase, the goal is for the patient to
14
resume normal functioning while continuing to
15
receive stable doses of medication. The patient
16
may remain on a specific dose for many months to
17
years. Without continued treatment, relapse rates
18
are very high, reaching 80 to 90 percent.
19
The expanded access allowed by DATA 2000 and
20
buprenorphine's favorable efficacy and safety
21
profile have contributed to its rapid uptake and
steady growth in use, and has allowed health care
1
practitioners to more fully treat their patients in
2
the office setting.
3
Shown here are the estimated numbers of
4
patients on Suboxone, Subutex, or any buprenorphine
5
product other than the transdermal buprenorphine
6
patch. Over one million patients are currently
7
receiving prescriptions.
8
With the success of buprenorphine, some
9
problems have emerged. Johanson and colleagues
10
summarized physician and patient knowledge of
11
buprenorphine misuse and diversion. Physicians who
12
are DATA 2000-trained and therefore waived to
13
prescribe buprenorphine for the treatment of opioid
14
dependence, report that with increasing
15
prescription, the number of physicians who know of
16
doctor-shopping to obtain larger quantities of
17
buprenorphine doubled between 2005 and 2009; who
18
know that buprenorphine is being sold on the street
19
nearly doubled; and that knowledge that
20
buprenorphine diversion, such that it is easier to
21
obtain illegally than is methadone, is increasing.
This knowledge and perception create a
1
dilemma for physicians, who don't want to be the
2
source of misuse and diversion when treating their
3
patients. Johanson's 2012 data further demonstrate
4
that patients are also aware that buprenorphine is
5
being sold on the street and is being used to get
6
high.
7
While the reports for methadone remained
8
fairly constant between 2005 and 2009, both street
9
sales and illicit buprenorphine use increased in
10
each of those years. Both physicians and patients
11
are aware of misuse and diversion of buprenorphine,
12
and so is the federal government.
13
While physicians have welcomed the
14
opportunity to treat more opioid-dependent
15
patients, they are burdened by the dilemma posed by
16
misuse and diversion. Patients, too, are concerned
17
that this problem may again restrict access.
18
Public health authorities and the general public
19
want this problem addressed and managed.
20
Also, the increasing availability of
21
sublingual buprenorphine has resulted in an
increase in buprenorphine ingestions by children
1
under the age of 6, as reported in the January 25th
2
morbidity and mortality report.
3
The report estimates that between 2010 and
4
2011, an average of approximately 1500 children
5
were seen in the emergency department. In a prior
6
report, almost 10 percent of hospitalizations for
7
drug ingestion in children are due to
8
buprenorphine/naloxone, even though buprenorphine
9
products amounted to only 2 percent of all retail
10
opioid prescriptions in that same year. This
11
represents a greater proportion than any other
12
single medication.
13
These statistics are among the most
14
compelling arguments for a new buprenorphine
15
formulation.
16
Probuphine's formulation is intended to
17
expand on buprenorphine's benefits for the
18
treatment of opioid dependence by minimizing the
19
risk of accidental ingestion, misuse, abuse, and
20
diversion, and by providing extended dosing.
21
The implant formulation must be administered
by a clinician and eliminates patient possession of
1
the medication until it is placed subdermally. The
2
implant also provides stable blood levels over six
3
months, and optimizes medication adherence.
4
Reduced pill burden and assurance that the dose
5
written is the dose taken may provide additional
6
benefits for the patient.
7
Ten years ago, buprenorphine revolutionized
8
the treatment of opioid dependence. And now, this
9
new formulation provides new opportunities for
10
physicians and our patients.
11
So which patients might benefit from
12
Probuphine? To reduce the risk of death and
13
disability in children, Probuphine may be a better
14
option for patients with young children in their
15
household.
16
To address concerns about abuse, misuse, and
17
diversion, Probuphine may be a better option for
18
patients with a history of diversion.
19
To address poor adherence and complaints
20
about periodic increases in craving and withdrawal,
21
Probuphine may be a better option to provide
patients with a stable blood level.
1
To address a lack of medical management
2
access, Probuphine may be a better option for
3
patients who have mobility issues, live in remote
4
locations, or those who live in urban wastelands
5
who would otherwise not seek medical care.
6
To address the inconvenience of carrying
7
medications that announce a patient's opioid
8
dependence and breach privacy, Probuphine may be
9
a better option for frequent travelers, who
10
sometimes would rather be withdrawn from
11
medications than be embarrassed at border
12
crossings.
13
To address the stable patient who has
14
demonstrated the responsibility to consult
15
appropriately, Probuphine may be a better option
16
for patients who require less frequent office
17
visits.
18
There are still hundreds of thousands of
19
patients with untreated opioid dependence outside
20
the current system of medical care, and as
21
physicians, we want to provide better care and
expand our reach to this unserved patient
1
population.
2
Dr. Kate Glassman-Beebe will now present the
3
pharmacokinetic and efficacy data from the clinical
4
studies of Probuphine.
5
Sponsor Presentation – Kate Glassman-Beebe 6
DR. GLASSMAN-BEEBE: Thank you,
7
Dr. Barthwell, and good morning. I'm Kate
8
Glassman-Beebe, executive vice president and chief
9
development officer with Titan. I'll be presenting
10
data from our clinical development program, which
11
demonstrate that Probuphine is efficacious for the
12
maintenance treatment of opioid dependence at the
13
proposed clinical dose.
14
The clinical development program for
15
Probuphine consisted of six studies. These
16
included one PK study and one comparative
17
bioavailability study. In addition, there were two
18
phase 3 randomized, placebo-controlled studies, one
19
of which included an open label exploratory group
20
that received sublingual buprenorphine. Each of
21
the controlled studies also had an open label
extension safety study.
1
We measured plasma buprenorphine
2
concentrations in all six clinical studies, and as
3
shown here, the plasma concentrations peak shortly
4
after insertion and gradually decline to
5
steady-state concentrations by day 28. At steady
6
state, we observed consistent plasma concentrations
7
in all of the studies.
8
In addition to plasma buprenorphine
9
concentrations, we evaluated Probuphine's efficacy
10
and safety in two randomized, double-blind, placebo
11
implant controlled studies, 805 and 806.
12
Study 805, a double-blind study, included
13
163 patients with opioid dependence who were
14
randomized to Probuphine or placebo implants in a
15
2-to-1 ratio.
16
Study 806 included 287 patients randomized
17
to Probuphine, placebo implants, or to the
18
exploratory, open label, control sublingual
19
buprenorphine, 12 to 16 milligrams a day. The
20
randomization ratios were 2-to-1-to-2, and the
21
implant groups were double-blinded to treatment
assignment.
1
In each study, patients first underwent
2
induction with sublingual buprenorphine to
3
establish tolerability and effectiveness within a
4
dose range of 12 to 16 milligrams a day. Patients
5
who were successfully inducted were then randomized
6
2 to 1 to receive Probuphine or placebo implants.
7
And at each study site, a trained physician
8
performed all implant procedures in an office
9
setting.
10
Patients returned to the research site three
11
times per week to provide urine samples for drug
12
testing, and all received twice-weekly,
manual-13
guided substance abuse counseling for the first 12
14
weeks, and weekly counseling for the last 12 weeks.
15
Patients were permitted to receive
16
sublingual buprenorphine rescue medication during
17
the treatment phase. And all patients underwent
18
assessments for safety, efficacy, and compliance at
19
scheduled intervals. At 24 weeks or at early
20
discontinuation, the implants were removed,
21
followed 2 to 4 weeks later by the final visit.
Patients who completed 24 weeks of treatment in
1
studies 805 and 806 were then eligible to enroll in
2
the open label extension studies, 807 and 811
3
respectively.
4
Patients on Probuphine or placebo were
5
required to receive a fifth implant if they needed
6
sublingual buprenorphine as rescue medication for 3
7
or more days over 2 consecutive weeks, or for 8 or
8
more days over 4 consecutive weeks. And then they
9
received a fifth implant.
10
In study 806, patients randomized to the
11
open label Suboxone group were required to receive
12
a dose between 12 and 16 milligrams a day.
13
Now moving to efficacy objectives,
14
endpoints, and analyses. In the treatment of
15
opioid dependence, successful treatment encompasses
16
many factors. For the purpose of the clinical
17
development program, we used urine testing for
18
opioids as the primary objective indicator of
19
efficacy, reporting the proportion of samples that
20
tested negative.
21
During the course of the development
program, we had discussions with the FDA to also
1
develop a method to incorporate patients'
self-2
reported drug use to corroborate urine drug
3
testing.
4
So for each patient, we collected urine for
5
opioid testing three times per week. The primary
6
outcome measure was the percentage of
opioid-7
negative urines. So for each patient treated, we
8
calculated the percentage of samples from week 1 to
9
week 24 that were negative for opioids.
10
Two imputations were performed. First, all
11
missing urine data were considered to be positive.
12
And second, if a patient reported opioid use but
13
the corresponding urine tested negative, the urine
14
result was considered to be positive. In other
15
words, patient positive self-reported opioid use
16
trumped negative urine opioid results.
17
These percentages were summarized and
18
displayed in the cumulative distribution function,
19
or CDF, for each treatment group. The primary
20
statistical analysis compared the CDFs using a
21
Wilcoxon test stratified by study site and gender.
The Wilcoxon test uses the percentiles displayed in
1
the CDF to compare the distributions. The
2
advantage of presenting the CDF over simple means
3
or medians is that it displays the data from all of
4
the patients, not just the average patient.
5
The secondary efficacy measures included
6
scores from three standard instruments that are
7
used to monitor symptoms of opioid withdrawal and
8
craving in a clinical setting -- the Subjective
9
Opiate Withdrawal Scale, or SOWS, the Clinical
10
Opioid Withdrawal Scale, abbreviated COWS, and the
11
opioid craving Visual Analog Scale, or VAS. We
12
also used the Clinical Global Impression scores,
13
which reflect patient-rated and observer-rated
14
severity of drug abuse.
15
We tested multiple secondary and exploratory
16
endpoints since efficacy for opioid dependence is
17
determined by many factors. As a control for
18
multiplicity, we prespecified a fixed sequence for
19
statistical testing. Each endpoint was tested only
20
if the preceding endpoints met statistical
21
significance at the alpha equals .05 level. I'll
show you the fixed sequence for each study with the
1
results.
2
Eligible patients were 18 to 65 years old
3
and met DSM-IV criteria for current opioid
4
dependence, and had not used medication-assisted
5
therapy for opioid dependence during the preceding
6
90 days.
7
The key exclusion criteria for both studies
8
included the diagnosis of AIDS or treatment with
9
protease inhibitors; diagnosis of a serious medical
10
or psychiatric disease; treatment with prescription
11
opioids for chronic pain; and significant
12
withdrawal symptoms or significant craving at the
13
end of the sublingual buprenorphine induction
14
period. We also excluded pregnant or lactating
15
women, and patients with a second DSM-IV
drug-16
related substance dependence diagnosis, with the
17
exception of nicotine and caffeine.
18
Now moving to results. Here are the patient
19
demographics for each study. The majority of
20
randomized patients were men, approximately
21
70 percent in study 805 and approximately
60 percent in study 806. The mean age range was 35
1
to 39. A majority of patients, 73 to 83 percent,
2
were Caucasian. And at baseline, 72 to 78 percent
3
of randomized patients reported that their opioid
4
dependence was diagnosed less than 5 years prior to
5
screening for the studies.
6
Heroin was most often reported as the
7
primary opioid of abuse in both studies, and
8
between 33 percent and 48 percent primarily abused
9
prescription opioids.
10
More than twice as many Probuphine patients
11
completed the studies as compared with placebo.
12
The proportions of patients who completed the
13
six-month studies, shown here, reflect the frequent
14
study dropouts that are typical in this patient
15
population; 65.7 percent and 64 percent of
16
Probuphine-treated patients remained on study for
17
the full six months. In contrast, fewer than
18
one-third of the patients randomized to placebo
19
implants completed the studies.
20
The reasons for early discontinuation in
21
studies 805 and 806 are shown here in order of
frequency in the 805 Probuphine group. Most of the
1
early discontinuations were due to treatment
2
failure in the placebo arm. In study 805, all
3
treatment failures occurred in the placebo group.
4
In study 806, only 5.3 percent of the Probuphine
5
group, compared with 17 percent in the placebo
6
group, were treatment failures.
7
Small numbers of patients in both treatment
8
groups withdrew due to noncompliance, patient
9
request, adverse events, and other reasons. One
10
patient assigned to Probuphine was discontinued
11
following a partial implant expulsion, and one
12
patient assigned to placebo discontinued due to
13
pregnancy.
14
I will first present the urine drug testing
15
results for study 805. The primary statistical
16
analysis of the urine drug tests used a cumulative
17
distribution function. To help explain the CDF
18
analysis, I'll show the proportion of patients with
19
opioid-negative urines as histograms of the
20
frequency distribution of the opioid-negative
21
urines. The proportion of patients on the Y axis
that had each decile of percent negative urines on
1
the X axis is shown for the Probuphine group.
2
For example, 10 percent of the patients in
3
the Probuphine group had 30 to 40 percent of their
4
urine samples negative for opioids over the 24-week
5
study period. Eight percent of patients had 90 to
6
100 percent of their urine samples negative for
7
opioids over that period. And the cumulative
8
distribution is constructed by adding each decile
9
to the sum of its preceding deciles. This creates
10
a cumulative distribution of the frequencies of
11
each percentage of opioid-negative urines.
12
The median value, where half of the patients
13
have a greater proportion of negative urines and
14
half have a lower proportion, can now be shown.
15
Using a more traditional display of the CDF, we see
16
the proportion of patients on the Y axis and the
17
percentage of opioid-negative urines on the X axis.
18
The CDF for the placebo group was
19
constructed in the same manner. According to the
20
prespecified Wilcoxon test of the CDF, Probuphine
21
was superior to placebo for the percentage of
opioid-negative urines, with a p value of .0142.
1
The median values were 13.9 percent
opioid-2
negative urines in the placebo implant group, and
3
29.4 percent in the Probuphine group. And I just
4
want to emphasize that the median is shown here and
5
not the mean, as is commonly shown in the
6
literature. Later I'll shown the means in an
7
exploratory analysis.
8
The CDF analysis that I just showed looked
9
at efficacy over the entire 24-week treatment
10
period. To illustrate how urine drug test results
11
compared at various times during the studies, we
12
performed an exploratory analysis and plotted the
13
mean fractions of urine samples that were negative
14
for opioids, shown on the Y axis, at 4-week
15
intervals throughout the study period, shown on the
16
X axis.
17
Subsequent to the first interval in study
18
805, the Probuphine group had consistently greater
19
proportions of opioid-negative urines than did the
20
placebo implant group. The differences between the
21
CDFs for opioid-negative urine results for
Probuphine and placebo implants were nominally
1
significant at all of the 4-week time intervals
2
except the first.
3
This supportive presentation of the data
4
illustrates that Probuphine's efficacy relative to
5
placebo spanned the entire six-month treatment
6
period in study 805, with mean percent negatives of
7
36 percent versus 22 percent respectively.
8
Moving to the urine opioid test results for
9
study 806, the CDF display for study 806 also shows
10
that Probuphine was superior to placebo with a
11
p value of less than .0001. The median for the
12
placebo implant group was 8.3 percent of urine
13
samples negative for opioids, and for the
14
Probuphine group, 20.3 percent opioid-negative
15
urines. And again, I want to emphasize that the
16
medians are shown here and not the means.
17
We also evaluated the efficacy at 4-week
18
intervals. Probuphine was consistently associated
19
with a greater proportion of opioid-negative urines
20
throughout the 24-week study. As we observed in
21
study 805, the differences between the CDFs for
opioid-negative urine results for Probuphine and
1
placebo implant were nominally significant at each
2
of the 4-week time intervals except the first, with
3
mean percent negatives of 36 percent versus
4
14 percent, respectively, over the 24-week
5
treatment period.
6
In the treatment of opioid dependence,
7
success can be measured by a number of factors in
8
addition to negative urine drug tests. So we
9
analyzed a panel of secondary endpoints that
10
included additional analyses of urine opioid tests:
11
study completion, abstinence from opioid use, and
12
patient- and clinician-rated measures of opioid
13
cravings and withdrawal.
14
We also analyzed the use of supplemental
15
sublingual buprenorphine. For each of the studies,
16
the key secondary and exploratory endpoints were
17
tested in a prespecified, fixed testing sequence.
18
Shown here is the testing sequence for
19
study 805. This diagram shows the effect size at
20
week 24 of Probuphine relative to placebo for the
21
secondary efficacy measures in order of the
prespecified testing for study 805. Results that
1
fall to the left of the vertical line favor
2
Probuphine, while those to the right favor placebo.
3
And as you can see, the point estimates all fall to
4
the left, favoring Probuphine.
5
The analysis of abstinence, defined as three
6
opioid-negative urines within a strictly-defined
7
study week, did not reach statistical significance
8
for weeks 1 to 16. So all of the statistical
9
measures at and below abstinence should be
10
considered exploratory in study 805.
11
The testing sequence for study 806 differed
12
slightly from study 805. First, the CDF of the
13
percent opioid-negative urines from weeks 1 to 16
14
was the primary endpoint in study 805, but is a key
15
secondary endpoint in study 806. And secondly, we
16
prespecified analyses of Probuphine compared with
17
the exploratory open label active comparator arm in
18
study 806.
19
Here are the secondary endpoint results for
20
study 806, presented from top to bottom in the
21
prespecified testing order. All effects favored
Probuphine, and all but one achieved statistical
1
significance relative to placebo.
2
Retention in treatment is a key predictor of
3
success in the treatment of opioid dependence. And
4
as I showed in the patient disposition summary,
5
more patients assigned to Probuphine completed
6
24 weeks of treatment than placebo patients.
7
Kaplan-Meier analysis confirmed that over
8
the 24-week treatment periods, the probability that
9
patients would complete treatment was significantly
10
greater with Probuphine than with placebo implants.
11
The p values were less than .0001 in both studies.
12
In the double-blind studies, 63 percent of
13
patients who were treated with four Probuphine
14
implants, and 45 percent of patients after
15
receiving a fifth Probuphine implant, took no
16
sublingual rescue medication.
17
In the open label studies, 79 percent of the
18
four-Probuphine-implant group, and 67 percent of
19
the five-Probuphine-implant group, took no
20
supplemental rescue medication. And finally, of 83
21
patients who completed both double-blind and open
label studies, 41, or 49 percent, took no
1
supplemental rescue medication over two sequential
2
24-week treatment periods.
3
As a reminder, both 805 and 806 featured
4
prespecified criteria for dose increases and
5
treatment failure based on the amount of sublingual
6
rescue medication taken by the patients. The
7
target dose of four Probuphine implants was
8
effective for most patients. Only 20 to 22 percent
9
of Probuphine patients required a dose increase to
10
five implants, compared with 39 to 58 percent of
11
placebo patients.
12
Treatment failure was defined as any patient
13
who received a fifth implant and continued to
14
require supplemental rescue buprenorphine, as I
15
just described. No Probuphine patients met
16
criteria for treatment failure in the 805 study,
17
and only six met the criteria in study 806. In the
18
placebo group, 29 percent and 17 percent were
19
treatment failures.
20
To put the rescue buprenorphine use during
21
the studies into perspective, we translated the
total amount of sublingual buprenorphine used
1
during study 806 into the equivalent number of
2
8 milligram tablets. Over the 24-week study, the
3
average Probuphine patient received the equivalent
4
of 5 buprenorphine tablets. The mean number of
5
sublingual buprenorphine 8 milligram tablet
6
equivalents provided as rescue to
Probuphine-7
treated patients was 98 percent less than the
8
mean number of tablets provided as treatment to the
9
open label sublingual buprenorphine group.
10
We also looked at other measures of efficacy
11
in the Probuphine treatment arm compared with the
12
exploratory open label sublingual
13
buprenorphine/naloxone arm. This exploratory
14
treatment arm allowed us to estimate the efficacy
15
of Probuphine relative to current standard
16
treatment.
17
Over the entire 24 weeks of treatment in
18
study 806, about one-third of urine samples in each
19
of the Probuphine and sublingual buprenorphine
20
treatment groups were opioid-negative, taking into
21
account patient self-reported opioid use. And
