1. Pharmacy
Track:
Impact
of
Abuse-­‐Deterrent
Formula;ons
Presenters:
Douglas
Throckmorton,
MD,
Deputy
Director
for
Regulatory
Programs,
Center
for
Drug
Evalua;on
and
Research,
FDA
Richard
C.
Dart,
MD,
PhD,
Director,
Rocky
Mountain
Poison
and
Drug
Center,
Professor,
University
of
Colorado
Moderator:
Peter
VanPelt,
RPh,
Associate
Director
for
Corporate
Alliances,
American
Pharmacists
Associa;on

2. Disclosures
• Douglas
Throckmorton
has
no
financial
conflicts
of
interest
to
disclose.
• Richard
Dart
has
financial
rela9onships
with
proprietary
en99es
that
produce
health
care
products
and
services.
These
financial
rela9onships
are
research
funding
from
McNeil
Consumer
Healthcare
and
Bioclon.
The
RADARS
System
is
financially
supported
by
subscrip9ons
from
most
pharmaceu9cal
companies
that
produce
prescrip9on
opioids
or
s9mulants.
All
rela9onships
are
with
Denver
Health
and
Hospital
Authority,
the
public
hospital
for
Denver,
Colorado.
Dr.
Dart
receives
no
individual
compensa9on.

3. Learning
Objec9ves
1. State
the
purpose
for
u9lizing
abuse-­‐
deterrent
formula9ons.
2. Analyze
emerging
trends
and
methods
for
evalua9ng
abuse-­‐deterrent
technologies.
3. Compare
data
of
prescribers
who
use
medica9ons
with
abuse-­‐deterrent
formula9ons
versus
medica9ons
without
these
technologies
and
the
rate
of
overdoses
associated.

4. April
21
–
23,
2014
MarrioR
Marque
Hotel
Atlanta
Georgia
Douglas C. Throckmorton MD
Deputy Director for Regulatory Programs
CDER, FDA

5. 5

6. Learning
Objec;ves
• Understand
the
history
of
abuse-­‐deterrent
opioid
development
• Understand
the
importance
and
challenges
of
developing
and
tes9ng
successful
abuse-­‐
deterrent
opioids
• Understand
the
importance
and
challenges
of
assessing
the
impact
of
abuse-­‐deterrent
opioids
6

7. Agenda
• FDA
work
to
support
the
development
of
abuse-­‐deterrent
formula9ons
of
opioids
– Abuse-­‐Deterrent
Opioids
DraY
Guidance
– Regulatory
decisions
• Progress
in
use
of
abuse-­‐deterrent
formula9ons
of
opioids
• Challenges
in
the
development
of
abuse-­‐
deterrent
formula9ons
of
opioids
7

8. Overall
Messages
• Important
work
has
been
done
to
encourage
the
development
and
use
of
successful
abuse-­‐
deterrent
formula9ons
of
opioids
– FDA
is
applying
principles
in
draY
Guidance
to
regulatory
decisions
– DraY
Guidance
is
s9mula9ng
new
development
– Meaningful
progress
requires
systema9c,
scien9fically
rigorous
and
flexible
approach
– Challenges
remain
before
any
one
abuse-­‐deterrent
technology
can
be
adopted
8

9. Overall
Messages
(cont)
• Work
on
ADF
development
is
one
part
of
the
FDA
efforts
to
confront
prescrip9on
drug
abuse
• Improving
drugs
used
to
treat
pain
o Abuse-­‐deterrent
formula9ons
of
opioids
o New
classes
of
pain
drugs
that
lack
abuse
risk
• Improving
safe
use
of
opioids
o Improved
educa9on
of
prescribers
and
pa9ents
to
reduce
risk
of
abuse
o Improved
surveillance
to
understand
use
of
opioids
o Improved
use
of
packaging
and
storage
of
opioids
• Improving
treatment
of
opioid
abuse
• Improving
treatment
of
opioid
overdose
o Naloxone
autoinjector
approval
9

10. “GUIDANCE
FOR
INDUSTRY
ABUSE
DETERRENT
OPIOIDS—EVALUATION
AND
LABELING”
10

11. DraU
Guidance
on
Abuse-­‐Deterrent
(AD)
Formula;ons
of
Opioids
• Early
experience
with
AD
formula9on
development
• Focus
of
development
on
crush-­‐resistant/
extrac9on-­‐resistant
technologies
and
addi9on
of
aversive
products
(e.g.,
soaps,
naloxone)
• No
broad
claims
for
abuse-­‐deterrence
in
labeling
• Some
studies
included
in
labeling
(e.g.,
Oxecta)
• No
robust
evalua9on
of
impact
of
the
formula9on
in
real
world
sedng

12. DraU
Guidance
on
AD
Opioid
Formula;ons
(cont)
• Follows
earlier
related
draY
Guidance:
“Assessment
of
Abuse
Poten9al
of
Drugs”,
issued
January
2010
• hRp://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInforma9on/Guidances/UCM198650.pdf
• Discusses
use
of
safety
informa9on
from
all
areas
of
the
NDA,
including
brief
discussion
of
abuse-­‐
deterrent
formula9ons
12

13. DraU
Guidance
on
AD
Opioid
Formula;ons
(cont)
• Ini9al
focus
is
on
opioids
• Part
of
work
to
create
safer
opioids
• Guidance
on
AD
formula9on
development
was
promised
as
part
of
ONDCP
Rx
Drug
Abuse
Plan
(2011)
• Guidance
on
ADF
development
mandated
under
FDASIA*
• Goal
date
January
9,
2013
* Food and Drug Administration Safety and Innovation Act

14. DraU
Guidance
on
AD
Opioid
Formula;ons:
Released
January,
2013
• Purpose:
Reflect
the
state
of
the
science
of
abuse
deterrence
(rela9vely
new),
and
the
need
for
flexible
approach
while
s9ll
applying
a
rigorous,
science-­‐based
standard
in
evalua9on
and
labeling
of
drugs
as
data
accumulates
14

15. DraU
Guidance
on
AD
Opioid
Formula;ons
:
Highlights
• Goals:
Two
over-­‐arching
goals:
– Encourage
the
development
of
successful
abuse-­‐
deterrent
formula9ons
of
opioids
– Assure
appropriate
development
and
availability
of
generic
drugs,
reflec9ng
their
importance
in
US
healthcare
• Accomplishing
Goal:
• Encouraging
development
of
successful
abuse-­‐
deterrent
formula9ons
through
accurate
labeling
15

16. Highlights
of
DraU
Guidance
on
AD
Opioid
Formula;ons
• Lays
out
development
roadmap:
– Scien9fic
studies
relevant
to
assessing
impact
of
formula9on
on
abuse
– Assessments
FDA
will
use
when
looking
at
study
data
• Lays
out
impact
of
AD
data
on
opioid
labeling,
including
claim
for
abuse-­‐deterrence
– Goal
to
incen9vize
meaningful
AD
formula9on
development
• Iden9fies
areas
of
addi9onal
scien9fic
needs
16

17. Labeling
Claims
for
Opioids
with
AD
Formula;ons
• Grouped
according
to
source
and
type
of
data
– Tier
1:
Physical/Chemical
Barriers
to
Abuse
• Examples:
data
on
crushing
and
extrac9on
– Tier
2:
PK
Data
• Clinical
serum
concentra9ons
(e.g.,
Tmax,
Cmax)
– Tier
3:
Demonstra9on
of
Reduced
Abuse
Poten9al
• Clinical
Abuse
Poten9al
Studies
– Tier
4:
Demonstra9on
of
Reduced
Abuse
• Postmarke9ng
data
on
use
and
misuse
of
marketed
product
• Differs
according
to
technology
used
to
create
formula9on
17

18. Addi;onal
Scien;fic
Work
Needed
• Characterizing
the
quan9ta9ve
link
between:
– Changes
in
the
pharmacokine9cs
of
opioids
in
different
formula9ons
– Results
of
clinical
studies
using
those
same
formula9ons
– Differences
in
abuse
in
the
community
• Characterizing
the
best
methods
to
analyze
clinical
data
on
abuse
• Characterizing
the
best
methods
to
analyze
the
impact
of
formula9ons
on
rates
of
abuse
in
the
community
18

19. Unresolved
Issues
• Does
not
address
how
FDA
will
approach
generic
drug
evalua9on,
approval,
and
withdrawal
• Does
not
set
‘bright
line’
standard
of
what
cons9tutes
meaningful
‘abuse
deterrence’
– Will
need
more
experience
before
we
can
set
such
a
standard
– Need
more
data
on
the
link
between
non-­‐clinical
and
pre-­‐
market
studies
and
post-­‐market
impact
on
abuse,
overdose,
and
death
19

20. Since
Release
of
DraU
Guidance
• Considerable
industry
interest
in
developing
AD
formula9ons
of
opioids
• Mul9ple
mee9ngs
with
FDA
and
manufacturers
• Importantly,
new
approaches
to
AD
opioid
development
are
being
proposed/tested,
in
addi9on
to
crush-­‐resistant/extrac9on-­‐
resistant
technologies

21. 1.
OXYCONTIN
AND
OPANA
ER
2.
EXTENDED-­‐RELEASE
AND
LONG-­‐ACTING
OPIOIDS
RELABELING
AND
POST-­‐MARKETING
REQUIREMENT
3.
ZOHYDRO
21

22. Ac;ons
on
Oxycon;n
&
Opana
ER
• April
16,
2013:
Oxycon9n
granted
labeling
as
abuse-­‐
deterrent
– The
new
labeling
indicates
that
the
product
has
physical
and
chemical
proper9es
that
are
expected
to
make
abuse
via
injec9on
difficult
and
to
reduce
abuse
via
the
intranasal
route
(snor9ng)
• May
10,
2013:
Opana
ER
determined
not
to
have
demonstrated
abuse-­‐deterrent
proper9es
• Decisions
based
on
scien9fic
data
from
each
applica9on
separately,
drawing
on
principles
from
draY
Guidance
22

23. Ac;on
on
Zohydro
• Zohydro
– Member
of
Extended-­‐Release/
Long-­‐Ac9ng
(ER-­‐LA)
Class
of
opioids
– Similar
doses,
an9cipated
risks
of
abuse
and
an9cipated
uses
as
other
ER-­‐LA
opioids
– Meets
statutory
requirements
for
approval
• Iden9fiable
benefits
for
pa9ents
and
prescribers
– Provides
addi9onal
choice
for
pa9ents
and
prescribers
– Allows
users
of
high
doses
of
hydrocodone
to
avoid
use
of
acetaminophen
and
liver
toxicity
and
take
fewer
pills
• Label
reflects
newly
revised
ER-­‐LA
opioid
labeling
– Responsive
to
Advisory
CommiRee
concerns
about
ER-­‐LA
opioids
– Increased
safety
informa9on
– New,
focused
indica9on
– Sponsor
is
required
to
conduct
addi9onal
studies
23

24. Ac;on
on
Zohydro:
Why
didn’t
FDA
require
AD
formula;on?
• Abuse-­‐deterrent
technologies
are
not
a
silver
bullet
and
are
s9ll
early
stages
of
development
– One
approved
product
that
is
abuse
deterrent
(Oxycon9n)
• Important
first
step,
but
abuse
of
Oxycon9n
s9ll
occurs
• Not
effec9ve
at
reducing
primary
route
of
abuse
(oral)
• Can
be
defeated
using
easily
available
means
– At
least
one
other
opioids
(Opana
ER)
that
incorporate
similar
technologies
designed
to
deter
abuse
failed
to
demonstrate
an
impact
on
abuse
• This
is
not
straighsorward!
– Premature
to
require
early
technology
when
what
is
needed
is
improved
science
and
technology

25. 25

26. Ongoing
Focus
on
AD
Formula;on
Development
• Con9nued
scien9fic
progress
• FDA
laboratory
working
on
AD
formula9on
science
• FDA
support
of
external
scien9fic
work
on
AD
formula9ons
• Con9nued
work
to
assess
impact
of
AD
formula9ons
on
actual
abuse
and
misuse
of
opioids
• FDA
epidemiologists
working
on
improving
tools
FDA
uses
to
assess
impact
of
AD
formula9on
of
Oxycon9n
in
US
market
• FDA
and
USG
working
to
improve
the
surveillance
databases
used
to
assess
impact
of
AD
formula9ons
in
US
market
• Refinement
of
our
guidance
on
the
development
of
ADFs:
• Pathway
to
the
development
of
ADFs
of
generic
drugs
• Refinement
of
what
is
needed
to
demonstrate
meaningful
abuse-­‐deterrence

27. Conclusions
• Important
work
has
been
done
to
encourage
the
development
and
use
of
successful
abuse-­‐deterrent
formula9ons
of
opioids
• Work
to
encourage
abuse-­‐deterrent
formula9ons
of
opioids
is
one
of
many
ac9vi9es
FDA
is
doing
to
improve
the
safe
use
of
opioid
drugs
• Improving
the
use
of
opioids
through
careful
and
appropriate
regula9ons,
including
labeling
• Improving
the
use
of
opioid
through
educa9on
• Improving
the
use
of
opioids
through
improved
science
• FDA
will
con9nue
to
act
with
the
available
data
to
seek
a
balance
between
the
needs
of
pain
pa9ents
and
the
need
to
reduce
prescrip9on
drug
abuse
27

28. Impact of Abuse-Deterrent Formulations
National Rx Drug Abuse Summit
Atlanta, Georgia
April 2014
Richard
C.
Dart,
MD,
PhD
Director,
Rocky
Mountain
Poison
and
Drug
Center
Professor,
University
of
Colorado

29. Disclosure
Statement
• "Richard
Dart
has
financial
rela9onships
with
proprietary
en99es
that
produce
health
care
products
and
services.”
• These
financial
rela9onships
are
research
funding
from
McNeil
Consumer
Healthcare
and
Bioclon.
• The
RADARS
System
is
financially
supported
by
subscrip9ons
from
most
pharmaceu9cal
companies
that
produce
prescrip9on
opioids
or
s9mulants.
• All
rela9onships
are
with
Denver
Health
and
Hospital
Authority,
the
public
hospital
for
Denver,
Colorado.
• Dr.
Dart
receives
no
individual
compensa9on.

30. 30
Total
US
Pharmaceu9cal
Opioid
Consump9on
1980
–
2010,
Morphine
Equivalents
(mg
per
capita)
http://ppsg-production.heroku.com/chart
800

31. 31
hRp://www.whitehouse.gov/blog/2014/02/10/5-­‐things-­‐know-­‐about-­‐opioid-­‐overdoses
England and Wales Drug Related Deaths 2001 - 2011
Total
Giraudon et al. Br J Clin Pharm 2013

32. FDA
DraY
Guidance
Abuse-­‐Deterrent
Opioids
-­‐
Evalua9on
and
Labeling
• Prescrip9on
opioid
analgesics
are
an
important
component
of
modern
pain
management.
• Abuse
and
misuse
of
these
products,
however,
have
created
a
serious
and
growing
public
health
problem.
• FDA
has
worked
to
address
this
problem
while
ensuring
that
pa9ents
in
pain
have
appropriate
access
to
opioid
analgesics.

33. Conflic9ng
Views
• …
FDA
advisory
commiRee
voted
against
approval
of
a
hydrocodone
product
lacking
tamper-­‐resistant
technology.
– "I
would
feel
very
uncomfortable
approving
a
non-­‐abuse-­‐
deterrent
product,"
one
of
the
panelists
said
at
the
9me.
• Andrew
Kolodny,
MD,
co-­‐founder
of
PROP,
expressed
concern
that
labeling
of
abuse-­‐resistant
products
could
contribute
to
false
marke9ng.
– "If
doctors
are
misled
to
believe
that
these
formula9ons
are
less
addic9ve,
and
if
they
develop
a
false
sense
of
security
about
these
products,
that
could
possibly
make
the
epidemic
worse,"
hRp://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/36782

34. Abuse
Deterrent
Formula9ons
in
the
United
States
34
OxyContin, Opana ER, Exalgo, Oxecta, Nucynta ER

35. Abuse
Deterrent
Formula9ons
Site
of
Ac9on
35
Swallow
Chew
Crush
Snort
Inject
Currently
Available
Can
ADFs
Decrease
Progression?

36. RADARS
System
Results
through
December
31,
2013
36
36

37. What
is
the
RADARS®
System?
• History
– Denver
Public
Safety
Net
Hospital
for
150
years
• State
sanc9oned
independent
authority
– Created
2001
by
Purdue
Pharma
– 2006,
Denver
Health
and
Hospital
Authority
(DHHA)
• Independent
program
– Mul9ple
pharmaceu9cal
subscribers
• Data
can
only
be
used
for
safety
repor9ng
• Conflict
of
interest
statement
– None,
other
than
running
system
for
DHHA
as
noted
above
37

38. Drug
Transactions
Criminal
Justice
250
agencies
49
states
Illicit
Market
Price
StreetRx.com
Users/Buyers
50
states
New
Initiates
College
Survey
2000
students
50
states
Entering
Treatment
SKIP
155
practices
47
states
Acute
Events
49
Poison
centers
46
states
Entering
Treatment
OTP
75
programs
37
states
Mosaic
Surveillance
for
Surveillance
of
Prescrip;on
Drug
Abuse

39. 39
Principal
Inves;gators
• Theodore
J.
Cicero,
PhD
Washington
University
at
St.
Louis
• Richard
C.
Dart,
MD,
PhD
Denver
Health
and
Hospital
Authority
• Hilary
SurraR,
PhD
Nova
Southeastern
University
• Mark
W.
Parrino,
MPA
American
Associa=on
for
the
Treatment
of
Opioid
Dependence
Law
Enforcement
• John
Burke
Na=onal
Associa=on
of
Drug
Diversion
Inves=gators
RADARS
System
Scien;fic
Advisory
Board
Substance
Abuse
Experts
• Herbert
D.
Kleber,
MD
Columbia
University
• Sidney
Schnoll,
MD,
PhD
Pinney
Associates
• George
E.
Woody,
MD
University
of
Pennsylvania
Epidemiology/Biosta;s;cs
• Edgar
Adams,
ScD
Covance
• Nabarun
Dasgupta,
MPH
Founder
–
Epidemico
• Alvaro
Muñoz,
PhD
Johns
Hopkins
University

40. Show
Me
The
Data
• Do
ADFs
decrease
abuse?
– OxyCon9n®
(polyethylene
oxide),
Opana
ER®
(Intac®),
Nucynta
ER
(Intac®)
– Exalgo®,
Oxecta®,
Embeda®
– Suboxone®,
buprenorphine/naloxone
combos
• Do
they
affect
outcome?
– Injec9on?
– Mortality?

41. RADARS
System
Schedule
II
Excluding
Oxycodone
ER
Popula9on
Rates
by
Program,
2009-­‐2013
41
0
1
2
3
4
5
20093
20094
20101
20102
20103
20104
20111
20112
20113
20114
20121
20122
20123
20124
20131
20132
20133
20134
Rateper100,000population
Year Quarter
Poison Center
Program
Drug Diversion
Program
Treatment Center
Program
College Survey
Program

42. 42
Model
for
Oxycodone
Extended
Release
RADARS
System
Poison
Centers
0
2007
0.15
0.25
0.35
2005
0.30
0.20
0.10
0.05
2011
2010
2009
Inten9onal
exposures
/100,000
pop.
New Formulation
All
Oxycodone
ER
95%
CI
Ineffective
Effective
October 21-22, 2010: Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee
and the Drug Safety and Risk Management Advisory Committee Meeting Announcement

43. ADFs–Demand
Reduc9on
People
Filling
Prescrip9ons
43
Before
AYer
ADF
AYer
ADF
Before
Oxycodone
ER
Oxymorphone
ER
Pre
Post
ADF
Pre
Post
ADF

44. Drug
Diversion
Program
Popula9on
Rate,
2009-­‐2013
44
*Other
opioids
excluding
ER
oxycodone
and
ER
oxymorphone.
Oxycodone
ER
Oxymorphone
ER
Other
Opioids

45. Poison
Center
Program
Popula9on
Rate,
2009-­‐2013
45
*Other
opioids
excluding
ER
oxycodone
and
ER
oxymorphone
Oxycodone
ER
Oxymorphone
ER
Other
Opioids

46. Poison
Center
Program
Route
of
Administra9on,
OxyCon9n

47. Rela9on
of
Original
OxyCon9n
and
Men9ons
in
Poison
Center
Program
Original
Formula;on

48. Case
Outcome
in
Poison
Center
Program
-­‐
Major
Outcome
or
Death
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0.045
0.05
Before
ADF
AUer
ADF
Before
ADF
AUer
ADF
OxyCon;n
Opana
ER
Rate
of
Major
Outcome
or
Death
Oxycodone
ER
Oxymorphone
ER

49. Treatment
Programs
Combined
2009-­‐2013
49*Other
opioids
excluding
ER
oxycodone
and
ER
oxymorphone.
Oxycodone
ER
Oxymorphone
ER
Other
Opioids

50. StreetRx.com
50

51. StreetRx, RADARS System Drug Diversion
and Silk Road – Price per milligram drug
51
Dasgupta, Suratt, et al, J Med Internet Res, 2013

52. US
StreetRx
Endorsement
of
Canadian
Oxycodone
Products
in
United
States
52
11
States
1
to
4
reports

53. Oxycodone
ER
in
US
and
Canada
Formula;on
United
States
Canada
Number
reports
Reported
Median
Price
per
mg,
US
Dollar
(range)
Number
reports
Reported
Median
Price
per
mg,
Canadian
Dollar
(range)
Crushable
“Old
OxyCon;n”
Apo-­‐Oxycodone
CR
24
1.00
(0.15
–
16.80)
1
1.00
(NR)
OxyCon;n®
93
1.00
(0.06
–
10.00)
16
1.00
(0.54
–
6.00)
Co-­‐Oxycodone
CR
11
1.00
(0.30
–
4.00)
0
NR
Teva-­‐Oxycodone
CR
4
0.88
(0.10
–
3.75)
0
NR
Average
1.00
1.00
Abuse
Deterrent
“New
OxyCon;n”
Oxycodone
ER
(OxyCon;n
in
US,
OxyNEO
in
Canada)
277
0.63
(0.03
–
10.00)
15
0.75
(0.38
–
1.40)
Average
0.63
0.75
RADARS
System
Technical
Report,
2014-­‐Q2

54. Other
Data
Sources
Navippro
Treatment
Centers
54
Butler
S,
et
al,
J
Pain
2012

55. Other
Data
Sources
Na9onal
Survey
of
Drug
Use
and
Health
Good
News
–
Bad
News
“The
number
of
persons
aged
12
or
older
who
were
current
nonmedical
users
of
the
pain
reliever
OxyCon9n
declined
from
566,000
in
2010
to
358,000
in
2012.”
55
NSDUH
2013

56. Yes,
Abuse
Deterrent
Formula9ons
Can
Reduce
the
Diversion
and
Abuse
of
an
Opioid
Analgesic,
but…
Some
Important
Ques9ons
Remain!
56

57. Squeezing
the
Balloon
Heroin
-­‐
Past
Month,
Past
Year
NSDUH
Report
2012
ADF
Oxycodone
ER

58. Can
ADFs
Bend
the
Curve?
• CS
–
College
Survey
DD
–
Drug
Diversion
• PC
–
Poison
Center
TC
–
Treatment
Centers
combined
• Methadone,
buprenorphine,
liquids,
injectables
excluded
0
0.5
1
1.5
2
2.5
3
CS DD PC TC
Rateper100,000population
The RADARS System
Average rate per 100,000 population by formulation
2013
ADF
ER
IR

59. Conclusions
• Formula9ons
that
resist
crushing
and
forming
injectable
solu9ons
can
reduce
diversion,
abuse
and
the
sequelae
of
abuse
of
that
par9cular
drug.
• The
poten9al
impact
of
ADF
technology
would
be
greater
if
more
products
used
technology.
• However,
the
“market”
will
adjust
to
the
new
barriers.
59

60. Thank
You!
60