Understanding FDA mandated animal behavioral pharmacology screening for drug abuse liability potential.

1. Abuse Liability Screening in Animals Understanding FDA Mandated Animal Behavioral Pharmacology Screening Paul J. Kruzich, Ph.D. Principal Consultant Preclinical Consulting Services, LLC www.preclinicalconsultingservices.com

2. Some General Backgroundfor the FDA Guidance Preclinical Consulting Services, LLC

3. 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”. *DraftGuidance 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 Preclinical Consulting Services, LLC

4. 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. Preclinical Consulting Services, LLC *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.

5. How does the FDA Classify Drugs as “Abuse Liable?” Preclinical Consulting Services, LLC

6. 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. Factors Leading to Labeling a Drug“Abuse Liable” Excerpted from the DraftGuidance for Industry Assessment of Abuse Potential of Drugs Preclinical Consulting Services, LLC

7. The 8 factors of 21 U.S.C. 811(c) The drug’s actual or relative potential for abuse Scientific evidence of the drug's pharmacological effects The state of current scientific knowledge regarding the drug or similar substances (e.g., class/mechanism of action) The drug’s history and current pattern of abuse Excerpted from the DraftGuidance for Industry Assessment of Abuse Potential of Drugs Preclinical Consulting Services, LLC

8. The 8 factors (cont.) The scope, duration, and significance of abuse What, if any, risk there is to the public health The drug’s psychic or physiological dependence liability Whether the substance is an immediate precursor of a substance already controlled. Excerpted from the DraftGuidance for Industry Assessment of Abuse Potential of Drugs Preclinical Consulting Services, LLC

9. 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). Excerpted from the DraftGuidance for Industry Assessment of Abuse Potential of Drugs Preclinical Consulting Services, LLC

10. 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. Excerpted from the DraftGuidance for Industry Assessment of Abuse Potential of Drugs Preclinical Consulting Services, LLC

11. 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. When Should an Abuse Potential Assessment be Submitted to FDA? (cont.) Excerpted from the DraftGuidance for Industry Assessment of Abuse Potential of Drugs Preclinical Consulting Services, LLC

12. 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 Preclinical Consulting Services, LLC

13. 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) Excerpted from the DraftGuidance for Industry Assessment of Abuse Potential of Drugs Preclinical Consulting Services, LLC

14. 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) Animal Abuse Liability Screening! Preclinical Consulting Services, LLC

15. Animal Behavioral Pharmacology for Abuse Screening Drug Discrimination Self-administration Preclinical Consulting Services, LLC

16. 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 Preclinical Consulting Services, LLC

17. 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 Preclinical Consulting Services, LLC

18. 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 Preclinical Consulting Services, LLC

19. Depiction of Inside wall of Drug Discrimination (operant) Chamber (what the animal sees) Pellet Dispenser Tube Saline Lever B Drug Lever A Pellet being dropped from dispenser/hopper into dish Food pellet reward in dispenser dish Preclinical Consulting Services, LLC

20. 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. Preclinical Consulting Services, LLC

21. 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.” Preclinical Consulting Services, LLC

22. 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 Preclinical Consulting Services, LLC

23. A Typical Rodent Drug Self-administration Chamber Setup Infusion Syringe Stimulus Light Catheter Infusion 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 Preclinical Consulting Services, LLC

24. Depiction of Inside wall of self-administration(operant) chamber (what the animal sees) Drug Lever Stimulus Light (to signal when an infusion is occurring) Preclinical Consulting Services, LLC

25. 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) Preclinical Consulting Services, LLC

26. 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) Preclinical Consulting Services, LLC

27. 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 Self-administration (cont.) Preclinical Consulting Services, LLC

28. 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.” Self-administration (cont.) Preclinical Consulting Services, LLC

29. Bibliography 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. 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) Controlled Substances Act (CSA), as amended February 15, 1996 (21 U.S.C. 801 et seq.). (http://www.justice.gov/dea/pubs/csa.html) DraftGuidance for Industry Assessment of Abuse Potential of Drugsprepared 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.pdf) KoobGF (2003) Drug Reward and Addiction. In Fundamental Neuroscience (2nd Ed) Academic Press; San Diego, CA 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) O'Connor EC, Chapman K, Butler P, Mead AN. The predictive validity of the rat self-administration model for abuse liability. NeurosciBiobehav Rev. 2011;35(3):912-38. (http://dx.doi.org/10.1016/j.neubiorev.2010.10.012) Preclinical Consulting Services, LLC

30. Contact Information Paul J. Kruzich, Ph.D. Principal Consultant Preclinical Consulting Services, LLC paul.kruzich@preclinicalconsultingservices.com www.preclinicalconsultingservices.com

31. Accompanying Commentary at: ToxInsights Toxicological Insights for the Global Pharmaceutical Community http://www.tigertox.com/2011/04/18/drug-abuse-liability-testing/