Government and Industry Response to Rx Abuse Robert Bianchi Prescription Drug Research Center - Chicago, IL Atlanta GA - April 7, 2015

DISCLAIMER Robert Bianchi has disclosed no relevant, real or apparent personal or professional financial relationships with proprietary entities that produce health care goods and services.

Learning Objectives Government response to the Rx drug abuse epidemic Industry Response to the Rx drug abuse epidemic FDA Guidance to Industry In vitro testing to evaluate abuse-deterrent opioids

Current Situation CDC has declared Rx abuse as an epidemic. More americans abuse Rx than cocaine, heroin, inhalants & hallucinogens COMBINED In 2013 approximately 43,982 overdose deaths occurred, one death every 12 min* Of these deaths, 22,767 (51.7%) were attributed to Rx drug abuse – 16,235 were attributed to opioids – 6,973 were attributed to benzodiazepines* *CDC Centers for Disease Control and Prevention. National Vital Statistics System mortality data. (2015)

Insatiable Appetite Rx abuse is the fastest growing drug problem in the United States (5% of world population) 65% of the worlds supply of hydromorphone (Dilaudid) 80% of the worlds supply of oxycodone (OxyContin) US consumed 99% of the worlds supply of hydrocodone (Vicodin)

What caused this phenomenon ? Prescription drugs do not fall under the clandestine cloud of illegal drugs such as heroin, ecstasy or methamphetamine Prescription drugs are more available due to the development of new products and increased prescriptions Rx drugs are safe - FDA approved & Dr. prescribed Friends and family use them Drugs are frequently obtained free of cost

Contributing Causes Doctor Shopping Over prescribing Stolen or forged prescriptions Pharmacy thefts Internet pharmacies Pain clinics

Pain Clinic aka Pill Mill

Pill Mill seizure

Industry Response Develop consortium to explore options and advise FDA Develop formulations that deter abuse Educate prescribers and patients Conduct research to develop new pain medications

Government Response Increased monitoring of –Manufactures –Distributors –Pharmacies –Doctors Prescription Drug Monitoring Programs DEA “Take Back Program” 309 tons of Rx medications from nine collection events Increased criminal investigations

Government Response Educational programs and publications for prescribers and patients Requires sponsors to develop REMS FDA issued draft guidance to industry in Jan 2013, describing how to demonstrate if an opioid formulation contains abuse deterrent properties. April 2013 FDA allows labeling concession to Purdue for reformulated OxyContin (physical or chemical properties that deter IV and nasal abuse). Original formulation available Encouragement to develop abuse resistant formulations (ADF)

ABUSE DETERRENT OPTIONS 1. Physical/Chemical barriers – Physical barriers can prevent chewing, crushing, cutting, grating, or grinding. Chemical barriers can resist extraction of the opioid using common solvents like water, alcohol, or other organic solvents. Physical and chemical barriers can change the physical form of an oral drug rendering it less amenable to abuse (e.g., reformulated OxyContin®)

ABUSE DETERRENT OPTIONS 2. Agonist/Antagonist combinations – An opioid antagonist can be added to interfere with, reduce, or defeat the euphoria associated with abuse. The antagonist can be sequestered and released only upon manipulation of the product. For example, a drug product may be formulated such that the substance that acts as an antagonist is not clinically active when the product is swallowed but becomes active if the product is crushed and injected or snorted. (e.g., Talwin Nx®, Suboxone, Embeda®)

ABUSE DETERRENT OPTIONS 3. Aversion – Substances can be combined to produce an unpleasant effect if the dosage form is manipulated prior to ingestion or a higher dosage than directed is used. (Oxecta oxycodone/niacin) 4. Prodrug – A prodrug that lacks opioid activity until transformed in the gastrointestinal tract. Can be unattractive for intravenous injection or intranasal routes of abuse (e.g. Vyvanse amphetamine).

ABUSE DETERRENT OPTIONS 5. Delivery System (including depot injectable formulations and implants) – Certain drug release designs or the method of drug delivery can offer resistance to abuse. For example, a sustained-release depot injectable formulation that is administered intramuscularly or a subcutaneous implant can be more difficult to manipulate. 6. Combination – Two or more of the above methods can be combined to deter abuse.

FDA GUIDANCE The Guidance describes four categories of recommended studies for supporting and evaluating claims of abuse-deterrence: –Premarket studies: Laboratory Manipulation and Extraction Studies (Category 1) Pharmacokinetic Studies (Category 2) Clinical Abuse Potential Studies (Category 3) -Post marketing Studies (Category 4)

Laboratory Manipulation and Extraction Studies Evaluate various simple and sophisticated mechanical and chemical ways a drug can be manipulated. (1) defeating or compromising the controlled release of an opioid from extended-release formulations (2) preparing an IR or ER formulation for alternative routes of administration (3) separating the opioid antagonist, if present, from the opioid agonist, thus compromising the product’s abuse-deterrent properties.

Laboratory Manipulation and Extraction Studies Evaluate resistance to manipulation 1. Ease of particle size reduction using commonly available manual tools (spoons, hammer, mortar & pestle) & electrical appliances (coffee grinder, blender) 2. Effects of heat & cold on manipulation efficiency

Coffee mills used to grind tablets Shown lids have been used for approx 15 runs each Examples on broken blades from two mills Photos by permission, Egalet, Copenhagen DK, 2010.

Laboratory Manipulation and Extraction Studies For a product with potential for snorting, the particle size distribution should be established. For a product with potential for snorting, the particle size distribution should be established, using various tools. Photo by permission, National Medical Services Laboratories (NMS) 2014

Laboratory Manipulation and Extraction Studies Evaluate extractability of intact & manipulated product 1.Commonly available aqueous solvents that have potentially relevant solvent characteristics (pH, polarity such as water, alcohol, cola, vinegar, acetone, mineral spirits) 2.Conduct at elevated temperature & room temperature. 3.Conduct on stirred & soaked comparator & ADF 4.Conduct on in tact and ground material

Extractability Photo by permission, National Medical Services Laboratories (NMS) 2014

SMOKING ABUSE For a product with potential for smoking, the vaporization temperature and degradation temperature of the opioid in salt and base form should be determined.

SMOKING APPARATUS Photo by permission, National Medical Services Laboratories (NMS) 2014

INTRAVENOUS ABUSE For a product with potential for intravenous injection, the opioid concentration in a small injection volume and the viscosity (syringeability and injectability) of the injection fluid should be determined.

INJECTABILITY Photos by permission, Egalet, Copenhagen DK, 2010.

INJECTABILITY Photo by permission, National Medical Services Laboratories (NMS) 2014

DOSE DUMPING The ingestion of alcoholic beverages with extended release opioids poses serious safety concerns i.e. uncontrolled immediate release of drug. The FDA now recommends in vitro drug release studies to determine if alcohol causes enhanced release of opioid using varying concentrations of alcohol

DOSE DUMPING Photo by permission, National Medical Services Laboratories (NMS) 2014

IN-VITRO EXPERIMENTS Develop written protocols that produce statistically valid, reproducible results. –Include related comparator product –Include controls –Include quality assurance procedures –All experiments must be conducted at least in triplicate –Use graphs and charts to illustrate data –Experiments should be conducted by an independent laboratory that is blinded to the fullest extent possible in addition to in house laboratory experiments –Take photographs to illustrate results

IN-VITRO EXPERIMENTS aka KITCHEN CHEMISTRY Every product is different; therefore each requires a unique set of experiments developed under the standardized tests to assess tamperability. Sponsor knows product’s vulnerabilities and should develop experiments in concert with abuse experts based on product knowledge and current abuse methods of similar products using commonly available chemicals and equipment. Standardized laboratory extractions must be developed for each dosage form, e.g. tablets, capsules, patches, liquids, IR, SR using solvents & equipment commonly available. Consider testing all dosage strengths

Summary No objective measure exists to measure tamperability/extractability Each product/system requires unique experiments designed to address vulnerabilities Use independent laboratory (NMS) & abuse experts Consider all modes of abuse & all strengths Include photographs, graphs & charts where appropriate No product has addressed multiple pill abuse No product has been proven to be tamper proof

Thank you Robert P. Bianchi Vice-President and Chief of Scientific and Technical affairs Prescription Drug Research Center 134 N. LaSalle Street Chicago, IL Office – Cell