Ph 3 throckmorton dart

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

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.

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.

April 21 – 23, 2014

MarrioR Marque Hotel Atlanta Georgia

Douglas C. Throckmorton MD Deputy Director for Regulatory Programs

CDER, FDA

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

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

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

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

“GUIDANCE FOR INDUSTRY ABUSE DETERRENT OPIOIDS—EVALUATION AND

LABELING”

10

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

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

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

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

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

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

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

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

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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

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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

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

21

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

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

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

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

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

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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

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

Total US Pharmaceu9cal Opioid Consump9on 1980 – 2010, Morphine Equivalents (mg per capita)

http://ppsg-production.heroku.com/chart

800

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

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.

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

Abuse Deterrent Formula9ons in the United States

34

OxyContin, Opana ER, Exalgo, Oxecta, Nucynta ER

Abuse Deterrent Formula9ons Site of Ac9on

35

Swallow

Chew

Crush

Snort

Inject

Currently Available

Can ADFs Decrease

Progression?

RADARS System Results through December 31, 2013

36 36

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

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

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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

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?

RADARS System Schedule II Excluding Oxycodone ER Popula9on

Rates by Program, 2009-‐2013

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0

1

2

3

4

5 20

093

2009

4 20

101

2010

2 20

103

2010

4 20

111

2011

2 20

113

2011

4 20

121

2012

2 20

123

2012

4 20

131

2013

2 20

133

2013

4

Rat

e pe

r 100

,000

pop

ulat

ion

Year Quarter

Poison Center Program

Drug Diversion Program

Treatment Center Program

College Survey Program

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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

Inten9

onal exposures /100,000 po

p.

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

ADFs–Demand Reduc9on People Filling Prescrip9ons

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Before AYer ADF AYer ADF Before

Oxycodone ER Oxymorphone ER

Pre Post ADF Pre Post ADF

Drug Diversion Program Popula9on Rate, 2009-‐2013

44 *Other opioids excluding ER oxycodone and ER oxymorphone.

Oxycodone ER Oxymorphone ER Other Opioids

Poison Center Program Popula9on Rate, 2009-‐2013

45 *Other opioids excluding ER oxycodone and ER oxymorphone


Poison Center Program Route of Administra9on, OxyCon9n

Rela9on of Original OxyCon9n and Men9ons in Poison Center Program

Original Formula;on

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 M

ajor Outcome or Death

Oxycodone ER Oxymorphone ER

Treatment Programs Combined 2009-‐2013

49 *Other opioids excluding ER oxycodone and ER oxymorphone.


StreetRx.com

50

StreetRx, RADARS System Drug Diversion and Silk Road – Price per milligram drug

51 Dasgupta, Suratt, et al, J Med Internet Res, 2013

US StreetRx Endorsement of Canadian Oxycodone Products

in United States

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11 States 1 to 4 reports

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

Other Data Sources Navippro Treatment Centers

54 Butler S, et al, J Pain 2012

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

Yes, Abuse Deterrent Formula9ons Can Reduce the Diversion and Abuse of an Opioid

Analgesic, but…

Some Important Ques9ons Remain!

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Squeezing the Balloon Heroin -‐ Past Month, Past Year

NSDUH Report 2012

ADF Oxycodone ER

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

Rat

e pe

r 100

,000

pop

ulat

ion

The RADARS System

Average rate per 100,000 population by formulation 2013

ADF

ER

IR

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.

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Thank You!

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Ph 3 throckmorton dart

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