Value of Abuse-Deterrent Opioids. For your personal use. Not for further distribution.

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1 Value of Abuse-Deterrent Opioids

2 HHS Data Show that Prescription Opioid Abuse Continues To Be a Serious Public Health Issue At least half of all opioid overdose deaths in the United States (US) involve a prescription opioid 1 Overdose deaths involving prescription opioids have quadrupled since 1999 From 1999 to 2014, prescription opioids have been associated with over 165,000 overdose related deaths in the US In 2014 alone: Prescription opioids led to over 14,000 overdose related deaths 1 Nearly 2 million people abused or were dependent on prescription pain relievers 2 Approximately 53% to 81% of people who die from prescription opioid overdoses have a history of pain. 3,4 HHS, US Department of Health and Human Services. 1. CDC Web site. Injury prevention & control: opioid overdose. Updated March 12, Accessed May 23, Data from Wide-ranging Online Data for Epidemiologic Research (WONDER) For your database. personal use. Not for further distribution. 2. SAMHSA. Results From the 2014 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-50, HHS Publication No. (SMA) Rockville, MD: SAMHSA; Paulozzi LJ et al. Addiction. 2009;104(9): Lanier WA et al. Pain Med. 2012;13(12):

3 Diversion of Prescription Pain Relievers: 2015 SAMHSA Data Misusers of Prescription Opioids Obtain the Opioid from Doctors over a Third of the time and over Half of the time from Family or Friends Prescription(s) from More than One Doctor, 1.7% Stolen Prescription(s), 0.7% Prescription(s) from One Doctor, 34.0% Other*, 12.0% From Friend or Relative, 54.0% *Other includes: Drug Dealer/Stranger, Internet, Wrote Fake Prescription, Stole from Doctor s Office/Clinic/Hospital/Pharmacy, and Some Other Way. SAMHSA. Results from the 2015 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-48, HHS Publication No. (SMA) Rockville, MD: SAMHSA; September 2015.

4 Standard of Care Urges Health Care Professionals To Initiate Opioid Risk Mitigation Strategies Intervention Identify at Risk Patients Deter Tampering Monitor Abuse & Diversion Treat Addiction Rescue Therapy Non-pharmacologic Risk-assessment tool Psychiatric assessment PDMP check UDT Treatment agreement Limited prescriptions Pill counts Referral/counseling Recovery program Pharmacologic ADOs Naloxone Antagonist PDMP, Prescription Drug Monitoring Program; UDT, urine drug testing. 1. Dowell D et al. MMWR Recomm Rep. 2016;65(1): Chou R et al. J Pain. J Pain. 2009;10(2): Chou R et al. J Pain. J Pain. 2009;10(2): Webster LR, Fine PG. J Pain. 2010;11(7): Gourlay DL et al. Pain Med. 2005;6(2): Agrof f CE, Kahan M, Sellers EM. J Opioid Manag. 2014; 10(2): Nuckols et al. Ann Intern Med. 2014; 160(1): 38-47

5 Frequently Employed Non-Pharmacologic Strategies Have Potential Limitations that Contribute to the Growing Need for Additional Mitigation Approaches Strategies Intended Use Potential Benefits Potential Limitations Risk Assessment Tools Screen for existing substance abuse, addiction potential, and overall risk for aberrant behavior before opioid therapy is initiated and potentially throughout treatment Identification of patients at high risk for opioid overdose or use disorder Identification of patients that will benefit from increased caution, monitoring, or interventions when risk factors are present. Failure to capture risk associated with: Differing populations, e.g. age and gender Mental and physical comorbidities History of legal issues ORT and SOAPP-R have low sensitivity PDMP Track prescribing and dispensing of controlled prescription drugs, providing critical information regarding a patient s use of these agents, e.g. daily dosage, number of prescriptions, prescriber, pharmacy provider Identify and monitor patients who might be at higher risk for opioid overdose or use disorder Identify and monitor patients that are doctor or pharmacy shopping Identify and monitor patients for higher opioid dosage per day PDMP programs differ in their policies and only contain state-specific data (no crosscommunication): 49 states have authorized PDMP utilization, but only a few States require a PDMP check before prescribing About half of primary care providers (PCP) report utilizing PDMPs UDT/UDS Detection of illegal and prescription drugs, as well as intention/accidental drug overdose; monitoring tools for treatment compliance Identify and monitor patients who might be misusing, abusing, or diverting UDS is easy to use on site PCP knowledge gap on result interpretation. UDT are associated with lag time which slows result turnaround time UDS have low sensitivity and only detect drug classes PDMP, Prescription Drug Monitoring Program; UDT, urine drug testing; HPLC: high-performance liquid chromatography. Operational in 49 states plus Guam *Gas chromotography and mass spectrometry may be used to request identification of specific substances Agroff CE, Kahan M, Sellers EM. J Opioid Manag. 2014; 10(2): Manasco AT et al. Pharmacoepidemiol Drug Saf Apr 8. doi: /pds [Epub ahead of print] Nuckols et al. Ann Intern Med. 2014; 160(1): Rutkow L et al. Health Aff (Millwood). 2015;34(3): Updated March 23, Accessed May 23, Markway EC, Baker SN. Orthopedics Nov;34(11): Accessed May 23, Paulozzi, L.J., Kilbourne, E.M., Desai, H.A., 2011a. Pain Med. 12, Li, J. E. Brady et al. Prescription drug monitoring and drug overdose mortality Injury Epidemiology. 1 (1) pp.; 2014 C. Delcher et al. Abrupt decline in oxycodone-caused mortality after implementation of Florida's Prescription Drug Monitoring Program Drug & Alcohol Dependence. 150 pp. 63-8; Reifler L et al. Pain Medicine. 2012;13(3):355-6.

6 The FDA is changing course on Prescription Opioids from Raising Awareness to Seeking Solutions The FDA has developed a comprehensive action plan with 4 main pillars Be more transparent and open. Improve communication with medical community. Improve the available information about opioids. Focus efforts on approving drugs that have the potential to help mitigate the crisis. Continue to prioritize new abuse-deterrent opioid (ADO) formulations 2 Explore and encourage development of more effective abuse-deterrent features 2 Establish guidelines for development of generic versions of ADOs 1,2 Increase scrutiny of proposed new non-ado formulations 2 Work to improve access to naloxone 1,2 FDA, US Food and Drug Administration. 1. Califf RM. Changing course: a new approach to opioid pain medication at FDA. February 5, Accessed May 23, Califf RM et al. N Engl J Med. 2016;374(15):

7 FDA Considers Development of Abuse-Deterrent Opioids To Be a High Public Health Priority Abuse-deterrent properties are defined as those shown to meaningfully deter abuse, even if they do not fully prevent it Abuse-deterrent technologies to date are intended to make: manipulation (crushing, chewing, dissolving, extracting) of the opioid more difficult, or the effect of the manipulated opioid less attractive or rewarding FDA guidance describes the studies to be conducted to demonstrate a given formulation has abuse-deterrent properties, how studies will be evaluated, and what labeling claims may be approved based on results. FDA remains supportive of ADO development FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA; Califf, Robert M., Janet Woodcock, and Stephen Ostroff. "A Proactive Response to Prescription Opioid Abuse." New England Journal of Medicine (2016). FDA Guidance Issued April One potentially important step towards the goal of creating safer opioid analgesics has been the development of opioids that are formulated to deter abuse. FDA considers the development of these products a high public health priority. FDA Guidance for Industry: Abuse- Deterrent Opioids Evaluation and Labeling (April 2015)

8 Where to Find Abuse-Deterrence Data and Labeling Refer to prescribing information section 9: DRUG ABUSE AND DEPENDENCE Includes descriptions and data regarding the specific product s abusedeterrent studies (will vary by product) If such information does not appear in a product s labeling under section 9, that product is not an ADO, by FDA standards The pharmacokinetic data demonstrate that crushing [Tradename] results in the simultaneous release and rapid absorption of opioid and antagonist. These data along with the results from oral and intranasal clinical abuse potential studies and a clinical abuse potential study of intravenous opioid and antagonist to simulate crushed [Tradename] indicate that [Tradename] has properties that are expected to deter abuse via the oral, intranasal, and intravenous routes. However, abuse of [Tradename] by these routes is still possible. Example of potential labeling for an ADO with category 2 and 3 data FDA. Guidance for Industry: Abuse-Deterrent Opioids Evaluation and Labeling. Rockville, MD: FDA; 2015.

9 Limited Real-World Data Suggests a Reduction in Frequency of Abuse with Extended-Release (ER) Oxycodone (ADO OxyContin )* Observation Data Source Time Frame Change, % Abuse rates (ICD-9-CM) Drug abuse related poison center exposures Diagnosed addiction rates per 100 person-years of opioid use (ICD-9-CM) Diagnosed addiction rates per 100 person-years of opioid use (ICD-9-CM) Truven Health Analytics medical and pharmacy claims 1 6 months prior, 6 months post -18 (P =.034) to -23 (P <.001) RADARS Poison Center 1 year prior, 2 years post -36 (P <.001) Exposures 2 MarketScan commercial 1 year prior, 3 years post -25 database 3 MarketScan commercial 1 year prior, 1 year post -27 (95% CI, database 4-37% to -16%) Drug diversion rates RADARS Drug Diversion 5 2 years prior, 18 months post -53 (P <.001) Drug price law enforcement RADARS Drug Diversion 5 Time of switch to 1 year post -22 (P =.002) Doctor-shopping rates IMS LRx longitudinal patient data 6 6 months prior, 6 months post -40 Self-reported abuse NAVIPPRO Drug Treatment 7 14 months prior, 20 months post -41 (P <.0001) Self-reported abuse RADARS Opioid Treatment 5.5 years prior, 3 years post Decreased Program 8 (% not reported) ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; NAVIPPRO, National Addictions Vigilance Intervention and Prevention Program; RADARS, Researched Abuse, Diversion and Addiction-Related Surveillance System. *Selected sources; other studies have been conducted but are not represented here. Commercially insured and Medicaid patients, respectively; no significant change in abuse rates among Medicare-eligible patients in this study. Rate of diagnosed addiction increased among patients dispensed other opioids. 1. Rossiter LF et al. J Med Econ. 2014;17(4): Coplan PM et al. Pharmacoepidemiol Drug Saf. 2013;22(12): Coplan P, Kadakia A. Poster presented at: College on Problems of Drug Dependence 77th Annual Scientific Meeting; June 13-18, 2015; Phoenix, AZ.. 4. Coplan P, Kadakia A. Pharmacoepidemiol Drug Saf. 2015;24(S1):27. Abstract Sev ertson SG et al. J Pain. 2013;14(10): Chilcoat H et al. J Pain. 2014;15(4, suppl):s10. Abstract Butler SF et al. J Pain. 2013;14(4): Dart RC et al. N Engl J Med. 2015;372(3):

10 Limited Real-World Data Suggests a Reduction in Frequency of Abuse with Extended-Release (ER) Oxycodone (ADO OxyContin )* Observation Data Source Time Frame Change, % Abuse rates (ICD-9-CM) Drug abuse related poison center exposures Diagnosed addiction rates per 100 person-years of opioid use (ICD-9-CM) Diagnosed addiction rates per 100 person-years of opioid use (ICD-9-CM) Truven Health Analytics medical and pharmacy claims 1 6 months prior, 6 months post -18 (P =.034) to -23 (P <.001) RADARS Poison Center 1 year prior, 2 years post -36 (P <.001) Exposures 2 MarketScan commercial 1 year prior, 3 years post -25 database 3 MarketScan commercial 1 year prior, 1 year post -27 (95% CI, database 4-37% to -16%) Drug diversion rates RADARS Drug Diversion 5 2 years prior, 18 months post -53 (P <.001) Drug price law enforcement RADARS Drug Diversion 5 Time of switch to 1 year post -22 (P =.002) Doctor-shopping rates IMS LRx longitudinal patient data 6 6 months prior, 6 months post -40 Self-reported abuse NAVIPPRO Drug Treatment 7 14 months prior, 20 months post -41 (P <.0001) Self-reported abuse RADARS Opioid Treatment 5.5 years prior, 3 years post Decreased Program 8 (% not reported) ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; NAVIPPRO, National Addictions Vigilance Intervention and Prevention Program; RADARS, Researched Abuse, Diversion and Addiction-Related Surveillance System. *Selected sources; other studies have been conducted but are not represented here. Commercially insured and Medicaid patients, respectively; no significant change in abuse rates among Medicare-eligible patients in this study. Rate of diagnosed addiction increased among patients dispensed other opioids. 1. Rossiter LF et al. J Med Econ. 2014;17(4): Coplan P, Kadakia A. Pharmacoepidemiol Drug Saf. 2015;24(S1):27. Abstract Coplan PM et al. Pharmacoepidemiol Drug Saf. 2013;22(12): Sev ertson SG et al. J Pain. 2013;14(10): Coplan P, Kadakia A. Poster presented at: College on Problems of Drug 6. Chilcoat H et al. J Pain. 2014;15(4, suppl):s10. Abstract 138. Dependence 77th Annual Scientific Meeting; June 13-18, 2015; Phoenix, AZ. 7. Butler SF et al. J Pain. 2013;14(4): Dart RC et al. N Engl J Med. 2015;372(3):

11 Drug Diversion Decreased Upon Introduction of ADO Oxycodone ER (ADO OxyContin ) - RADARS Introduction of ADO Oxycontin Reported reduction in abuse rates following the reformulation of Oxycodone ER (ADO Oxycontin) do not predict the potential reduction of abuse rates of other abuse deterrent products Severtson et al., J Pain, Vol 14, No 10 (October), 2013: pp

12 Prescribing ER ADOs Instead of ER Non-ADOs Was Associated with a Reduction in Misuse/Abuse and NNH Objective: To estimate the change in health care resource utilization, associated costs, and number needed to harm (NNH) associated with prescribing ER non-ados compared to ADOs in a chronic pain population (N = 10,000) treated for a 12-month period of time. Methods: The reduction of misuse and/or abuse events and associated costs resulting from a physician s decision to prescribe an ER ADO instead of an ER non-ado to chronic pain patients was estimated through a decision model analysis. Key Results: Effect of ER Non-ADO and ADO Formulations on Misuse/Abuse Population* Non-ADOs: Number Needed to Harm ADOs: Misuse/Abuse Events Avoided Commercial Medicare Medicaid Veterans Health Administration Note: Number needed to harm is an epidemiologic measure that in this context indicates the number of patients exposed to an ER non-ado before a misuse and/or abuse-related event can be expected, that would not occur with an ER ADO. ER, extended release. *Range of results by population is due to the variability in abuse rates reported in claims databases for these populations. White AG et al. Presented at: ISPOR 21st Annual International Meeting; May 21-25, 2016; Washington, DC. Poster PSY36.

13 Analysis of Clinical Abuse Potential Study Data and Nonmedical Use: Impact on Healthcare Utilization and Cost A post-hoc analysis of clinical abuse potential studies and nonmedical use data resulted in significant associations between: Reductions in overall drug liking (5-point reduction) Decreased nonmedical use rates (2%-11%) Reduced private payer cost for a morphine ($ million) and oxycodone ($ million) ADF 1 Based on this analysis, a model was developed to determine the medical and economic impact of replacing the non-ado ER opioid market with ADOs This model predicted a 13%-31% reduction in abuse-related medical events and annual medical cost savings of up to $1.3 billion 2 * *Excludes drug costs; total net savings will depend on ADO price relative to non-ados. 1. White AG at al. J Opioid Manag. 2015;11(3): White A et al. J Pain. 2016;17(4, suppl):s41. Abstract 263.

14 Summary: Why ADOs? There is no single solution to the prescription opioid epidemic; it requires a comprehensive strategy Currently implemented interventions (ie, PDMP, UDT, ADO) in addressing opioid abuse are still lacking in effectiveness data and have limitations As a pharmacologic intervention, ADOs have properties that are expected to deter abuse, as established by clinical data reviewed by the FDA Real world data suggests a reduction in frequency of abuse with extended-release (ER) oxycodone ADOs should be considered as part of a multipronged approach to reduce opioid abuse in appropriate patients