Pjk abuse liability screening 02 aug-12

Understanding FDA Mandated Animal
Behavioral Pharmacology Screening

Paul J. Kruzich, Ph.D.
Principal Consultant
Preclinical Consulting Services, LLC
pkruzich@yahoo.com

Some General Background
for the FDA Guidance


What is “Abuse Potential?”

 Abuse potential *when a drug is used in nonmedical
situations, repeatedly or even sporadically, for the positive
psychoactive effects it produces, it is characterized as
“abuse potential”.

*Draft Guidance for Industry Assessment of Abuse Potential of Drugs prepared
by the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and
Research (CDER) at the Food and Drug Administration


Common Characteristics of
Abused Drugs*
 Central nervous system (CNS) activity, including:
 sedation
 euphoria
 perceptual and other cognitive distortions
 hallucinations
 mood changes
 Drugs with abuse potential often (but not always)
produce psychic or physical dependence and may lead
to the disorder of addiction.
*Excerpted from Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep.
No. 91-1444, 91st Cong., Sess. 1 (1970), reprinted in 1970 U.S.C.C.A.N. 4566, 4603.

How does the FDA Classify Drugs as
“Abuse Liable?”


Factors Leading to Labeling a Drug
“Abuse Liable”
 Under 21 U.S.C. 811(b) of the Controlled Substances
Act (CSA), the Secretary of Health and Human
Services is required to consider, in a scientific and
medical evaluation, 8 factors determinative of control
under the CSA.

 Following consideration of the 8 factors, the Secretary
must make 3 findings and a recommendation for
scheduling a substance in the CSA.
Excerpted from the Draft Guidance for Industry Assessment of Abuse Potential of Drugs


The 8 factors of 21 U.S.C. 811(c)
1. The drug’s actual or relative potential for abuse
2. Scientific evidence of the drug's pharmacological
effects
3. The state of current scientific knowledge regarding
the drug or similar substances (e.g.,
class/mechanism of action)
4. The drug’s history and current pattern of abuse



The 8 factors (cont.)
5. The scope, duration, and significance of abuse

6. What, if any, risk there is to the public health

7. The drug’s psychic or physiological dependence
liability

8. Whether the substance is an immediate precursor of
a substance already controlled.



A Sponsor’s Mandate
 If the drug has a potential for abuse, the sponsor must
submit “a description and analysis of studies or
information related to abuse of the drug, including a
proposal for scheduling, under the Controlled
Substances Act.” (21 CFR 314.50(d)(5)(vii)).

 A description must be submitted “of any studies
related to overdosage, etc. including information on
antidotes, or other treatments, if known” (id.) in the
new drug application (NDA).


When Should an Abuse Potential
Assessment Be Submitted to FDA?
 A sponsor must submit in the NDA an assessment of
studies and other information related to the potential
abuse of a drug when:
 the drug affects the central nervous system (CNS)
 the drug is chemically or pharmacologically similar to
other abused drugs
 the new drug produces psychoactive effects such as
sedation, euphoria, and mood changes.



When Should an Abuse Potential
Assessment be Submitted to FDA? (cont.)
 An assessment of abuse potential may be needed for
new (novel) drugs, including new molecular entities
(NME).
 For a marketed drug product that presents an
unexpected adverse event profile that includes events
that are related to abuse potential or that is being re-
evaluated for a new route of administration that could
affect the abuse potential of the drug.


What Should be Included in an
Abuse Potential Submission?
 A summary, interpretation, and discussion of abuse
potential data provided in the NDA

 A proposal and rationale for placing (or not placing) a
drug into a particular schedule of the Controlled
Substances Act


What Should Be Included in an Abuse
Potential Submission? (cont.)
 All primary data related to the abuse potential
characterization of the drug, organized under the following
subheadings:
 Chemistry
 Preclinical Pharmacology
 Animal Behavioral and Dependence Pharmacology
 Pharmacokinetics/Pharmacodynamics
 Human Abuse Potential Laboratory Studies
 Clinical Trial Data Relative to Abuse and Dependence Potential
 Integrated Summaries of Safety and Efficacy
 Foreign Experience with the Drug (Adverse Events, Abuse Potential,
Marketing, and Labeling)

What Should Be Included in an Abuse
Potential Submission? (cont.)
 All primary data related to the abuse potential
characterization of the drug, organized under the following
subheadings: Animal Abuse
 Chemistry Liability
 Preclinical Pharmacology Screening!
 Animal Behavioral and Dependence Pharmacology
 Pharmacokinetics/Pharmacodynamics
 Human Abuse Potential Laboratory Studies
 Clinical Trial Data Relative to Abuse and Dependence
Potential
 Integrated Summaries of Safety and Efficacy
 Foreign Experience with the Drug (Adverse Events, Abuse
Potential, Marketing and Labeling)


Animal Behavioral Pharmacology for
Abuse Screening
 Drug Discrimination

 Self-administration


Drug Discrimination
 Provides a behavioral indication of a drug’s
pharmacological mechanism of action in an intact
animal (usually rats or nonhuman primates)

 It does not specifically provide an index of whether or
not a drug will be abused. Rather, it provides an
indication of whether or not it’s pharmacological
actions are similar to other “reference” abused drugs
See Carter and Griffiths 2009 and Mansback et al 2003
for excellent reviews


Drug Discrimination Procedures
 Animals are trained to discriminate between a reference drug that creates a
change in internal state (e.g., amphetamine—the reference drug should have a
similar mechanism of action or chemistry as the novel compound) and an inert
vehicle (e.g., saline) in an operant task
 “Motivated” (food or water restricted) animals are trained to press levers to
receive a “reward” (a tasty food pellet or fruit juice)
 A computer tracks the number of responses made and rewards earned

 Following lever training, animals are then administered the reference drug and
trained to press “Lever A” in order to receive a reward—several rewards can be
earned during a session
 Responding of “Lever B” (saline) results in no reward

 The next session/day animals are administered an inert vehicle and trained to
press “Lever B” in an operant chamber in order to receive a reward
 Pressing “Lever A” on a saline day results in no reward


A Standard Drug Discrimination
Apparatus
Food
Hopper

Rat
Here

Response
Lever

Adapted from Med Associates © Copyright Med Associates Inc., 1998-2011. All Rights Reserved—
Preclinical Consulting Services has no association with Med Associates


Depiction of Inside wall of Drug Discrimination
(operant) Chamber (what the animal sees)
Pellet
Dispenser
Tube
Drug Saline
Lever A Lever B

Pellet being dropped
Food pellet reward from dispenser/hopper
in dispenser dish into dish

Drug Discrimination Procedures (cont.)
 Over days, the number of accurate lever presses necessary
to receive the “reward” is increased to ensure accuracy
 The animal administered the reference drug must press Lever
A 10 times in a row and avoid pressing Lever B during the 10
consecutive responses
 The increased requirement serves as an index of specificity/accuracy

 Once the animal has demonstrated accurate discrimination
between the reference drug and saline, testing is initiated
with the novel compound.


Drug Discrimination Procedures (cont.)
 During testing, the animal is administered the novel compound

 Based on its response pattern, the animal “tells” the researcher
whether the novel compound is similar to the reference
compound or inert vehicle (there is no “correct” or “incorrect”
response).
 The animal does this by responding on the “drug” or “vehicle” lever—
either lever will deliver a reward during a “test” session.

 If the novel compound induces a similar internal “cue” or
interoceptive effect that is similar to the reference drug (the
animal responds on the “drug” lever) the novel compound must
be considered “abuse liable.”


Self-Administration
 Rodents and nonhuman primates will self-administer
most drugs of abuse that humans self-administer (see
O'Connor et al 2011 for excellent review)

 Animals (typically rats, occasionally nonhuman
primates) are implanted with indwelling intravenous
catheters


A Typical Rodent Drug Self-
administration Chamber Setup
Infusion
Syringe

Stimulus Catheter Infusion
Light Line
Rat
Here

Response Lever

Adapted from Med Associates © Copyright Med Associates Inc., 1998-2011. All Rights Reserved—
Preclinical Consulting Services has no association with Med Associates

Depiction of Inside wall of self-administration(operant)
chamber (what the animal sees)

Drug
Lever
Stimulus Light
(to signal when
an infusion is
occurring)


Self-Administration (cont.)
 Through behavioral techniques, animals are trained to
self-administer (lever press/remotely administer)
several intravenous infusions of a reference drug of
abuse (e.g., amphetamine) during daily sessions
 The number of allowable infusions (to protect from overdose,
self-administered infusions are controlled and recorded by a
computer)

 The reference drug should be in the same class or have
a similar mechanism of action as the novel compound
(based on established pharmacology and chemistry)


Self-administration (cont.)
 Once the animal is reliably self-administering the reference drug (based on
established criteria), the reference drug is removed from the infusion syringes
and replaced with saline the next day
 Animals will not self-administer saline
 After a day of saline access, the animals are given access to the training
drug again the next day

 After several alternating daily reference drug/saline sessions, very reliable and
robust patterns of behavior will occur:
 When the syringe is loaded with the reference drug, animals will show
good response for drug (e.g., make several [hundred] responses for drug)

 When the syringe is loaded with saline, the animal will almost
immediately stop responding within the first minutes of a daily
saline/vehicle session (animals make significantly fewer responses
compared to drug days)


 Once reliable patterns of behavior are established, a
dose response curve is generated for the reference drug
 Animals typically compensate for lower doses by self-
administering more infusions; doses higher than the
training doses are self-administered, but fewer
administrations are taken per session
 This dose-response pattern has been describe as an “inverted
U” (Koob 2003)
 If the dose is too low, experienced animals will not self-
administer that particular dose, much like saline


 Once the complete dose response curve of the reference
drug is generated, novel compound screening occurs:
 Different doses of the novel compound are provided to
animals on “test” days

 Test days are interspersed between normal reference drug and
saline days

 If the experimental animal self-administers the novel
compound based on a previously determined set of criteria,
the compound is considered “abuse liable.”


Bibliography
1. American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine
Consensus Document. Definitions related to the use of opioids for the treatment of pain, 2001.
http//www.painmed.org/pdf/definition.pdf.
2. Carter LP, Griffiths RR. Principles of laboratory assessment of drug abuse liability and implications for
clinical development. Drug Alcohol Depend. 2009 Dec 1;105 Suppl 1:S14-25. (http://bit.ly/fK1d0y)
3. Controlled Substances Act (CSA), as amended February 15, 1996 (21 U.S.C. 801 et seq.).
(http://www.justice.gov/dea/pubs/csa.html)
4. Draft Guidance for Industry Assessment of Abuse Potential of Drugs prepared by the Controlled
Substance Staff (CSS) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration.
(www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pd
f)
5. Koob GF (2003) Drug Reward and Addiction. In Fundamental Neuroscience (2nd Ed) Academic Press;
San Diego, CA
6. Mansbach RS, Feltner DE, Gold LH, Schnoll SH. Incorporating the assessment of abuse liability into the
drug discovery and development process. Drug Alcohol Depend. 2003;70:S73–85. (http://bit.ly/gHo0uV)
7. O'Connor EC, Chapman K, Butler P, Mead AN. The predictive validity of the rat self-administration model
for abuse liability. Neurosci Biobehav Rev. 2011;35(3):912-38.
(http://dx.doi.org/10.1016/j.neubiorev.2010.10.012)


Contact Information
Paul J. Kruzich, Ph.D.
Principal Consultant
 pkruzich@yahoo.com

Pjk abuse liability screening 02 aug-12

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