Properties Work in the Real World? November 16, 2016 Richard C. - - PowerPoint PPT Presentation

Abuse Deterrent Formulations: Testing effectiveness from the benchtop to real world

Do Medications with Abuse Deterrent Properties Work in the Real World?

November 16, 2016

Richard C. Dart, MD, PhD Director, Rocky Mountain Poison and Drug Center Professor, University of Colorado School of Medicine

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Judging by the size and frequency of the droppings, I’d say we’ve found the campaign trail.

ADFs in the Real World

• Category 4

– Epidemiological evaluation – Evaluates the performance of the product in the real world – No product has yet requested Category 4 designation

• Methods of deterring abuse

– OxyContin (oxycodone) and Arymo (morphine) use a physical-chemical approach that produces a tablet that is hard to crush and forms a thick gel with water. – Embeda (morphine) uses naltrexone as an antagonist to reduce the desired drug effect if the product is crushed. – Xtampza (oxycodone) uses a proprietary waxy microsphere that is difficult to crush or solubilize.

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• Strength (effect size)
• Consistency (reproducibility)
• Specificity
• Temporality (Effect has to occur after the cause)
• Biological gradient
• Plausibility
• Coherence
• Experiment
• Analogy
• Confounding factors

Hill Criteria: Do ADFs Work in the Real World?

• A plausible mechanism between cause and

effect is helpful

– but understanding of the mechanism is limited by current knowledge

Hill Criteria: Plausibility

Hill AB. Proc Royal Soc Med 1965;58:295-300.

• Prescription drug abuse is like other drug abuse, except

with an additional “route” of abuse: – Oral = intact + chewed or crushed – Intranasal – Intravenous

• Importance of manipulating drug

– Crucial transition

• Changes perception of heroin use1

– Risk of acute (overdose, death) and chronic events (addiction, infections, death) higher after intranasal or IV abuse than oral abuse

Scientific Basis of Abuse-Deterrent Opioids

• 1. Vosburg. J Child Adol Subst Abuse 2016.

Dart RC, Iwanicki JL. Can J Diag 2015;32:10.

Biological Plausibility

Death

Outcomes

Addiction Overdose

Filling the Balloon

Chewed Crushed Intact

Recreational Abuser Person in Pain

Susceptible Person

Death

Recreational Abuser

Dart RC, Iwanicki JL. Can J Diag 2015;32:10.

Person in Pain

Outcomes

Emptying the Balloon

Chewed Crushed Intact

Susceptible Person

Intervening in Prescription Drug Abuse

Addiction Overdose

Guidelines P D M P A D F A D F A D F A D F

• Effect has to occur after the cause

(including a delay, if expected)

• Minimal delay expected for oxycodone ER

– All drug shipped after August 9, 2010 was reformulated version – Pharmacy turnover of opioids is rapid

• Only oxycodone ER has adequate data to

evaluate effectiveness

Hill Criteria: Temporality

Hill AB. Proc Royal Soc Med 1965;58:295-300.

Researched Abuse, Diversion and Addiction- Related Surveillance (RADARS System)

DHHA

RMPDC RADARS System

History

– 2002, launched by Purdue Pharma – 2006, Denver Health and Hospital Authority takes independent ownership

– Denver Public Hospital for 150 years – State sanctioned independent authority

Conflict of Interest Statement

• Most manufacturers of prescription opioids or stimulants subscribe to RADARS

System.

• Subscribers receive information, but do not participate in developing the

System, data collection, or analysis of the data. They do not have access to the raw data.

• Employees are prohibited from personal financial relationships with any other

company.

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Mosaic Surveillance

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Temporality: Oxycodone ER Prescriptions Decreased Promptly After Reformulation

IMS, 2015

• 50%
• 40%
• 30%
• 20%
• 10%

0% 10% 20% 30%

Reformulation of Oxycodone ER

Other Opioids Oxycodone ER % Change in Prescriptions Dispensed Other Opioids = Oral dosage forms of opioid analgesics: hydrocodone, hydromorphone, morphine, oxymorphone, tramadol, tapentadol, and IR oxycodone 2011 2012 2013 2014 2015 2016

Temporality: Oxycodone ER Abuse and Diversion, Adjusted for Population, 2010–2016

• A small association does not mean that there is

not a causal effect, though the larger the association, the more likely that it is causal.

Hill Criteria: Effect Size

Hill AB. Proc Royal Soc Med 1965;58:295-300.

Effect Size: Oxycodone ER Abuse and Diversion, Adjusted for Population, 2010-2016

• Consistent findings observed by different

persons in different places with different samples strengthens the likelihood of an effect

Hill Criteria: Consistency

• 100%
• 50%

0% 50% 100%

Consistency: Oxycodone ER Associated with Lower Rates Across Many Data Sources

Outcome Source Pre vs. Post % Change [95% CI] Since Reformulation Misuse

RADARS (Poison Centers)

Abuse

RADARS (Poison Centers) NPDS (Poison Centers) NAVIPPRO (Treatment Centers) RADARS SKIP (Treatment Centers) RADARS OTP (Treatment Centers)

Opioid Use Disorder Database of Opioid Users (Marketscan) Overdose

Database of Opioid Users (Marketscan)

Diversion

RADARS (Drug Diversion)

Doctor Shopping

IMS Prescription Data

Decrease Increase

Coplan et al. Clin Pharmacol Ther. 2016.

Data adjusted for prescription volume

ER Oxycodone Other Opioids

0.4 0.8 1.2 1.6 2 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

National Survey of Drug Use and Health, OxyContin Nonmedical Use

# Cases

• f Past Year

Nonmedical OxyContin Use (in millions)

Reformulated Oxycodone ER

0.005 0.01 0.015 0.02 0.025 0.03 0.035 20094 20102 20104 20112 20114 20122 20124 20132 20134 20142

OxyC ER

Poison Center : Response to Reformulation

• f Oxycodone ER (OxyContin)

0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08

OxyC ER

Oxycodone ER Oxymorphone ER

Rate per 100,000 population

Reformulation of: OxyM ER Reformulation of: OxyM ER

• The more specific an association between a

factor and an effect is, the bigger the probability

• f a causal relationship1
• Results specific to oxycodone ER compared to
• ther analgesic opioids

Hill Criteria: Specificity

• 1. Hill AB. Proc Royal Soc Med 1965;58:295-300.

0.02 0.04 0.06 0.08 0.1 0.12 0.2 0.4 0.6 0.8 20031 20041 20051 20061 20071 20081 20091 20101 20111 20121 20131 20141 20151 20161

Per 100,000 Population Per 100,000 Population

Alternate Explanations Fail the Hill Temporality and Specificity Criteria

Reformulation FL TIRF

REMS ER/LA REMS

WA Rx Guidelines Natl Drug Take Back

NY/ACEP Rx Guidelines

HC-APAP Tramadol

PDMP Initiation

All Other Opioids Oxycodone ER

What Will Capture Category 4?

March is one of the peculiarly dangerous months to speculate…

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“The others are July, January, April, October, May, November, June, September, December, August and February.”

FDA Guidance on ADFs

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• Demonstrate abuse-deterrent properties “meaningfully

deter abuse, even if they do not fully prevent abuse”

– Abuse: intentional, non-therapeutic use of a drug or substance, even once, to achieve a desirable psychological or physiological effect

• “Results in meaningful reductions in abuse, misuse,

and related adverse clinical outcomes, including addiction, overdose, and death in the post-approval setting”

• Add to the totality of evidence to support ADF claim

• Specificity, consistency and effect size indicate

that abuse deterrent opioids are likely to be effective in reducing abuse and its outcomes

• Similar effects for crush-resistant oxymorphone

ER

• Widespread use would reduce prices and

reduce the crucial transition from intact swallowing to crushing

• Education, training, and other interventions

needed as well

Conclusions and Implications