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

Judging by the size and frequency of the droppings, I’d say we’ve found the campaign trail. 2

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. 3

Hill Criteria: Do ADFs Work in the Real World? • Strength (effect size) • Consistency (reproducibility) • Specificity • Temporality (Effect has to occur after the cause) • Biological gradient • Plausibility • Coherence • Experiment • Analogy • Confounding factors

Hill Criteria: Plausibility • A plausible mechanism between cause and effect is helpful – but understanding of the mechanism is limited by current knowledge Hill AB. Proc Royal Soc Med 1965;58:295-300.

Scientific Basis of Abuse-Deterrent Opioids • 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 use 1 – Risk of acute (overdose, death) and chronic events (addiction, infections, death) higher after intranasal or IV abuse than oral abuse 1. Vosburg. J Child Adol Subst Abuse 2016.

Biological Plausibility Filling the Balloon Person in Pain Outcomes Susceptible Person Intact Chewed Crushed Addiction Overdose Recreational Abuser Death Dart RC, Iwanicki JL. Can J Diag 2015;32:10.

Intervening in Prescription Drug Abuse Emptying the Balloon Person in Pain Guidelines A A P D D Outcomes Susceptible D F F Person M Intact Chewed Crushed Addiction P A Overdose Recreational D Abuser F Death A D F Dart RC, Iwanicki JL. Can J Diag 2015;32:10.

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

Researched Abuse, Diversion and Addiction- Related Surveillance (RADARS System) History DHHA – 2002, launched by Purdue Pharma – 2006, Denver Health and Hospital RMPDC Authority takes independent ownership – Denver Public Hospital for 150 years – State sanctioned independent authority RADARS System 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. 10

Mosaic Surveillance 11

Temporality: Oxycodone ER Prescriptions Decreased Promptly After Reformulation 30% 20% Other Opioids 10% 0% % Change in Prescriptions -10% Dispensed -20% Oxycodone ER -30% -40% Reformulation of Oxycodone ER -50% 2013 2014 2016 2011 2012 2015 Other Opioids = Oral dosage forms of opioid analgesics: hydrocodone, hydromorphone, morphine, oxymorphone, tramadol, tapentadol, and IR oxycodone IMS, 2015

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

Hill Criteria: Effect Size • 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 AB. Proc Royal Soc Med 1965;58:295-300.

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

Hill Criteria: Consistency • Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect

Consistency: Oxycodone ER Associated with Lower Rates Across Many Data Sources Pre vs. Post % Change [95% CI] Outcome Source Since Reformulation Misuse RADARS (Poison Centers) ER Oxycodone Other Opioids RADARS (Poison Centers) NPDS (Poison Centers) NAVIPPRO (Treatment Centers) Abuse 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 -100% -50% 0% 50% 100% Data adjusted for prescription volume Decrease Increase Coplan et al. Clin Pharmacol Ther. 2016 .

National Survey of Drug Use and Health, OxyContin Nonmedical Use Reformulated Oxycodone ER 2 1.6 # Cases of Past Year 1.2 Nonmedical OxyContin Use 0.8 (in millions) 0.4 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Poison Center : Response to Reformulation of Oxycodone ER (OxyContin) Oxycodone ER Oxymorphone ER Reformulation of: Reformulation of: OxyC ER OxyM ER OxyC ER OxyM ER 0.08 0.035 0.07 0.03 0.06 Rate per 0.025 100,000 0.05 population 0.02 0.04 0.015 0.03 0.01 0.02 0.005 0.01 0 0 20094 20102 20104 20112 20114 20122 20124 20132 20134 20142

Hill Criteria: Specificity • The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship 1 • Results specific to oxycodone ER compared to other analgesic opioids 1. Hill AB. Proc Royal Soc Med 1965;58:295-300.

Alternate Explanations Fail the Hill Temporality and Specificity Criteria Reformulation 0.8 0.12 HC-APAP FL TIRF WA Rx Tramadol REMS Guidelines 0.1 ER/LA Oxycodone ER Natl Drug REMS 0.6 Take Back Per 100,000 Population Per 100,000 Population All Other Opioids 0.08 NY/ACEP Rx 0.4 0.06 Guidelines 0.04 0.2 0.02 0 0 20031 20041 20051 20061 20071 20081 20091 20101 20111 20121 20131 20141 20151 20161 PDMP Initiation

What Will Capture Category 4? “The others are March is one of the peculiarly July, January, April, dangerous months October, May, to speculate… November, June, September, December, August and February.” 22

FDA Guidance on ADFs • 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 23

Conclusions and Implications • 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