Download PRE0004 - PDRC | Prescription Drug Research Center

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 - 2010
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 1995-2010
• 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. using various tools.
established,
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 60602
312-726-8620 - Office
571-233-4780 – Cell
[email protected]
[email protected]