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Abuse Liability Guidance - Nonclinical Drug Development

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Abuse Liability Guidance and Its Impact: How The Revised Guidance Affects Nonclinical Drug Development

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Abuse Liability Guidance - Nonclinical Drug Development

  1. 1. ®®® Abuse Liability Guidance and Its Impact: How The Revised Guidance Affects Nonclinical Drug Development Paul J. Kruzich, 1 Paul J. Kruzich, PhD, DSP, DABT Aclairo
  2. 2. ® Presentation Outline—A Nonclinical Perspective • Past Guidance (2010) • Changes with the New Guidance • Implications for Future Work • Strategy Suggestions 2Paul J. Kruzich
  3. 3. ® Assessment of Abuse Potential of Drugs: Guidance for Industry (2010) • The previous guidance was draft 2010 – 2017. – Any drug product that has central nervous system (CNS) penetrance and/or activity likely will have to be evaluated for abuse potential • Non-clinical studies were not required to be GLP • Sex of animals not specified • No explicit instructions on study designs • The “Big 3” non-clinical studies: – Physical Dependence – Drug Discrimination – Intravenous Self-Administration 3Paul J. Kruzich
  4. 4. ® • Was released end of January 2017 • Definitions are similar for 2010 and 2017 guidance • Any drug product that has central nervous system (CNS) penetrance and/or activity likely will have to be evaluated for abuse potential • Major metabolites (10% of total drug exposure) likely will need evaluation • Pharmacokinetics and absorption – Be mindful of drugs with rapid onset and clearance • Next steps if determined a package should be conducted: – The “Big 3” still major nonclinical focus (Physical Dependence, Drug Discrimination, and Intravenous Self-Administration) 4 Assessment of Abuse Potential of Drugs: Guidance for Industry (2017) Paul J. Kruzich
  5. 5. ® Changes in 2017 Guidance that Will Affect the Nonclinical Package • Specific mention that “it is appropriate to use” both sexes • All comparator and control drugs should be scheduled • The schedule of reinforcement (FR10) is explicitly stated “should be conducted using a standard FR10…” (this is a procedural/study design issue) • Application of Good Laboratory Practice (GLP) “must be” conducted. 5Paul J. Kruzich
  6. 6. ® Changes in 2017 Guidance that Will Affect the Nonclinical Package • Specific mention that “it is appropriate to use” both sexes (page 15!) • All comparator and control drugs should be scheduled • The schedule of reinforcement (FR10) is explicitly stated “should be conducted using a standard FR10…” • Application of Good Laboratory Practice (GLP) “must be” conducted. 6Paul J. Kruzich
  7. 7. ® Use of Both Sexes • Increased cost • Potential variability due to estrous cycle and indication of drug/drug class (e.g. psychostimulants) • Does CRO have experience with both sexes? • Have seen both scenarios (forced to go with both and arguing out of both) 7Paul J. Kruzich
  8. 8. ® Changes in 2017 Guidance that Will Affect the Nonclinical Package • Specific mention that “it is appropriate to use” both sexes • All comparator and positive control drugs should be scheduled (negative control is the vehicle) • The schedule of reinforcement (FR10) is explicitly stated “should be conducted using a standard FR10…” • Application of Good Laboratory Practice (GLP) “must be” conducted. 8Paul J. Kruzich
  9. 9. ® Scheduled Comparators • Need to ensure in similar or defendable class • Wording in Guidance is “should” –may be a point of negotiation but recent statements suggest otherwise • e.g. (nicotine) 9Paul J. Kruzich
  10. 10. ® Changes in 2017 Guidance that Will Affect the Nonclinical Package • Specific mention that “it is appropriate to use” both sexes (page 15!) • All comparator and control drugs should be scheduled • The schedule of reinforcement (FR10) is explicitly stated “should be conducted using a standard FR10…” (an example of specific design requirements, included power analyses) • Application of Good Laboratory Practice (GLP) “must be” conducted. 10Paul J. Kruzich
  11. 11. ® Study Designs • Be aware of the framework described in guidance (e.g. schedule of reinforcement, testing conditions). • Submit draft protocols to CSS prior to starting • Have a clear and defendable rationale for study design 11Paul J. Kruzich
  12. 12. ® Changes in 2017 Guidance that Will Affect the Nonclinical Package • Specific mention that “it is appropriate to use” both sexes (page 15!) • All comparator and control drugs should be scheduled • The schedule of reinforcement (FR10) is explicitly stated “should be conducted using a standard FR10…” (an example of specific design requirements, included power analyses) • Application of Good Laboratory Practice (GLP) “must be” conducted. 12Paul J. Kruzich
  13. 13. ® GLP’s • Make sure the laboratory is equipped for GLP studies (not as many available = more time) • QA site visit/auditing now requisite • Study Monitoring for protocol compliance • Part 11 compliance • SEND 13Paul J. Kruzich
  14. 14. ® Animal Behavioral Studies: When? • Timing is usually at the end of Phase 2/pre-Phase 3 meeting • The clinically relevant exposures must be known • Chemistry and receptor binding should be determined • Studies to run include Modified Irwin, Drug Discrimination, Self-Administration, and Physical Dependence 14Paul J. Kruzich
  15. 15. ® What Next? • Be prepared! – Time – Budget • Submit draft protocols to the Controlled Substance Staff prior to starting studies – A response can take several weeks to months • Have a formal discussion with FDA and CSS to discuss proposed designs – Have them state whether or not they view the designs as appropriate • Start your program 15Paul J. Kruzich
  16. 16. ® Assessment of Abuse Potential of Drugs: Guidance for Industry (2017) Paul J. Kruzich, PhD, DSP, DABT Aclairo PDG, Inc. 16Paul J. Kruzich

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