25/03/2014. Workshop Overview. Hot Topics in FDA Regulations and Pharmacotherapy Research that Impact Patient Care:

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1 Hot Topics in FDA Regulations and Pharmacotherapy Research that Impact Patient Care: Sharon L. Walsh, Ph.D. Shanna Babalonis, Ph.D. Michelle Lofwall, M.D. Center on Drug and Alcohol Research Department of Behavioral Science University of Kentucky American Society of Addiction Medicine Orlando, Florida April 11, 214 Workshop Overview Background on abuse liability, scheduling in the CSA, and regulatory authority Current status and recent FDA decisions on opioid products with a focus on extendedrelease and abuse deterrent products Review recent findings from the human laboratory on tramadol and oxymorphone Intersections between patient care and public policy: OxyContin and tramadol Hot Topics in FDA Regulations and Pharmacotherapy Research that Impact Patient Care: Introductory Presentation Sharon L. Walsh, Ph.D. Center on Drug and Alcohol Research Department of Behavioral Science University of Kentucky American Society of Addiction Medicine Orlando, Florida April 11, 214 1

2 Name ASAM Disclosure of Relevant Financial Relationships Content of Activity: ASAM Medical Scientific Conference 213 Commercial Interests Relevant Financial Relationships: What Was Received Relevant Financial Relationships: For What Role Sharon Walsh PCM Scientific Honoraria CME Lectures and Development of Educational Materals MedSignals, Inc. Consulting Fee Collaboration on development of medication adherence device DemeRx Consulting Fee Consulting on Novel Entity for Substance Abuse Treatment Eli Lilly, Inc. Consulting Fee Advisor on Abuse Liability Testing for Pipleline Products Astra Zeneca Consulting Fee Advisor for Mock FDA meeting Outline Define abuse potential, abuse liability and regulatory drug control Describe specific concerns related to extendedrelease opioid formulations Discuss key issues related to route of administration for drug misuse Review the current status of abuse deterrent product development Abuse Potential vs. Abuse Liability Abuse Potential Characterizes the ability of a CNS-active drug to produce positive psychoactive effects may include sedation, euphoria, perceptual and other cognitive distortions, hallucinations and mood changes. These effects are viewed as correlated with or predictive of the risk of abuse and/or addiction 2

3 Abuse Potential vs. Abuse Liability Abuse Liability Is similar and sometimes used interchangeably Includes abuse potential Captures other factors, including ease of synthesis and drug abuse/diversion history Describes abuse potential in a social and public health context * Recommendations for scheduling can be made on the basis of abuse potential findings in the absence of evidence of actual abuse How Are They Measured? Abuse Potential: Non-humans Measured in the Laboratory self-administration physical dependence testing Humans drug administration studies Abuse Liability: Measured also in Community Surveillance data from various reporting sources, including hospitals, treatment centers, national surveys, medical examiner deaths FDA Draft Guidance January 21 Data from human abuse potential studies will contribute to the development of product labeling and drug scheduling recommendations. If the human abuse potential studies and the adverse events profile from clinical studies do not show the presence of rewarding effects or other abuse-related behaviors or similar pharmacology, a recommendation for scheduling would be unlikely. What if the clinical studies do show evidence? 3

4 Scheduling: Controlled Substances Act Schedule I (heroin, marijuana) no accepted medical use/ high abuse potential Schedule II (amphetamine, oxycodone) High abuse potential, severe psychological or physical dependence Schedule III (steroids, ketamine, GHB) Abuse potential less than Schedule I and II, Low/moderate physical dependence, high psychological dependence Schedule IV (benzodiazepines, butorphanol) Low abuse potential, limited psychological or physical dependence Schedule V (codeine preps, pregabilin) Same as Schedule IV but less Scheduling: Why Does It Matter Depending on the Schedule (II-V), controls may include manufacturing and production quotas, varying degrees of manufacturing and distribution site security requirements, dispensing and prescribing limitations, a range of record-keeping and reporting requirements, and import/export regulations. The more restrictively scheduled- the more costly to manufacture and sell and the less accessible it is to prescribers and patients Which Drugs Need Evaluation? Drugs with abuse potential generally include drugs that affect the central nervous system, drugs that are chemically or pharmacologically similar to other drugs with known abuse potential, and drugs that produce psychoactive effects such as sedation, euphoria, or mood change FDA Draft Guidance- January, 21 4

5 Opioid Analgesic Formulations Immediate-release formulations account for the majority of written prescriptions (more than 8% of the U.S. market) There are fewer marketed extended-release formulations and they are prescribed less frequently (recommended only for opioid tolerant patients with chronic pain) Why are they raising a greater concern? Extended-Release (ER) Products Hydromorphone (Exalgo ) Morphine Products MS Contin Avinza Kadian ± 8 additional generics Nucynta ER (Tapentadol) 5

6 Extended Release May Translate to High Potency Dose Unit Convenient for Abuse Original OxyContin Crushed and Insufflated 6 Concentration (ng/ml) IN OxyContin 3 mg/7 kg IN OxyContin 15 mg/7 kg IV oxycodone 5 mg/7 kg Time (hrs) Lofwall, Moody, Fang and Walsh (211) J Clin Pharmacol, 52: Oxycodone Concentrations 6 Concentration (ng/ml) IN OxyContin 3 mg/7 kg IN OxyContin 15 mg/7 kg IV oxycodone 5 mg/7 kg Time (hrs) Lofwall, Moody, Fang and Walsh (211), J Clin Pharmacol, 52:

7 How Much Do You Like the Drug? Oxycontin (intranasal) mg/7 kg 15 mg/7 kg 3 mg/7 kg Oxycodone (p.o.) Placebo 1 mg 2 mg 4 mg Score B B Time (hrs) Time (hrs) Lofwall, Nuzzo & Walsh (212) Drug and Alcohol Dependence, 123: Walsh, Nuzzo, Lofwall & Holtman (28) Drug and Alcohol Dependence, 98: Intranasal Oral Plasma t max ~6 min Plasma t max ~6-9 min Bioavailability ~76% Bioavailability ~6% 6 Concentration (ng/ml) IN OxyContin 3 mg/7 kg IN OxyContin 15 mg/7 kg IV oxycodone 5 mg/7 kg Time (hrs) Lofwall, Moody, Fang and Walsh (211), J Clin Pharmacol, 52: Consequences of Intranasal Opioid Abuse: Nasal Septal Abcess Pulia M.S. & Reiff C. (214) J Emergency Medicine, e-pub ahead of print. 7

8 Zohydro First single-entity hydrocodone product marketed in the US Approved in October, 213 (despite FDA advisory panel voting against approval) Approval came one day after the FDA issued a decision to move all hydrocodone combination products from Schedule III to Schedule II Others are on the way. The FDA Move Towards Abuse Deterrent Formulations (ADFs) Abuse deterrent Abuse Proof FDA is encouraging pharma to invest in R & D to develop ADFs What is the incentive? Fast track approval Extended patent protection To obtain specific language in the label that would indicate some protective advantage against abuse? What evidence is needed? Can it be obtained only post-marketing? Types of Abuse Deterrent Formulations Tamper Proof (or Tamper Resistant) Relies on mechanical deterrence- devising a formulation resistant to extraction by crushing, heat, freezing, boiling What does this deter? May deter crushing for use by another route (intranasal or iv) May deter dose dumping (converting an ER dose into an IR dose) It does not deter oral abuse- the most common route of abuse 8

9 Oxycontin Reformulated Cicero, Ellis & Surratt (212) New England Journal of Medicine, 367: Oxycontin Reformulated Cicero, Ellis & Surratt (212) New England Journal of Medicine, 367: Opana ER Reformulated (Oxymorphone) A.K.A. The O-Bomb Manufacturer pulled original ER formulation and replaced with the reformulated ADF version Next, they petitioned the FDA to disallow any generic competitors to introduce a non-adf version on the basis of safety 9

10 FDA Response 5/1/213 While there is an increased ability of the reformulated version of Opana ER to resist crushing relative to the original formulation, study data show that the reformulated version s extended-release features can be compromised when subjected to other forms of manipulation, such as cutting, grinding, or chewing, followed by swallowing. Reformulated Opana ER can be readily prepared for injection, despite Endo s claim that these tablets have resistance to aqueous extraction (i.e., poor syringeability). It also appears that reformulated Opana ER can be prepared for snorting using commonly available tools and methods. Abuse Deterrent Formulations Tamper proof Inclusion of an antagonist Capitalizes on low bioavailability or sequestration of the antagonist when taken by the intended route of administration Morphine/Naltrexone (Embeda ) Buprenorphine/Naloxone (Suboxone ) Does the Drug Have Any Good Effects? 1 Visual Analog Rating Placebo Sublingual Intramuscular /.25 2/.5 4/1 8/2 16/4 1/.25 2/.5 4/1 8/2 16/4 Sublingual Intramuscular Buprenorphine/Naloxone Stoller, Bigelow, Walsh & Strain (21) Psychopharmacology, 154:

11 Does the Drug Have Any Bad Effects? 1 75 Visual Analog Rating /.25 4/1 16/4 2/.5 8/2 1/ /.5 8/2 4/1 16/4 Sublingual Intramuscular Buprenorphine/Naloxone Stoller, Bigelow, Walsh & Strain (21) Psychopharmacology, 154: Abuse Deterrent Formulations Tamper proof Inclusion of an antagonist Inclusion of an aversive agent Niacin Sodium lauryl sulfate Proprietary additives Oxecta - Immediate release oxycodone with both gelling properties (to preclude injection) and aversive additives aimed primarily at prevent snorting Oxecta : Crushed Intranasal Administration Definitely would 1 Crushed Oxecta 15 mg LS Mean VAS Score (95% CI) Neutral Crushed IRO 15 mg Definitely would not Overall Drug Liking Take Drug Again Assessment Schoedel et al. (212) J Opioid Management, 8:

12 What Does the FDA Require for Approval of a New ADF Formulation? Human Abuse Liability Studies (as usual) Bioequivalence Tamper Proof Studies Pharmacodynamic data and all pharmacokinetic parameters (i.e., T max, C max, AUC, bioavailability) that inform the relative resistance to manipulation by examination of drug exposure after dosing when the drug is: Swallowed whole, Crushed and swallowed, Crushed and snorted, Crushed and smoked, Crushed, dissolved and injected What Does the FDA Require for Approval of a New ADF Formulation? Inclusion of an antagonist Pharmacokinetic data demonstrating the differential bioavailability of the antagonist by different routes and Pharmacodynamic data that illustrate the consequences of the drug experience Inclusion of an aversive agent Safety and tolerability data Bioavailability of aversive agent Pharmacodynamic consequences of exposure to the aversive agent on the drug experience Summary Numerous strategies are being implemented to decrease misuse of opioid analgesics Individual and class-wide REMS Development of abuse-deterrent formulations Simultaneously, new name brand and generic opioid formulations continue to gain FDA approval and enter the market, including new IR products and ER products without ADF features This poses continued challenges for addiction and pain physicians and for federal regulators 12