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®®®
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
®
Presentation Outline—A
Nonclinical Perspective
• Past Guidance (2010)
• Changes with the New Guidance
• Implications for Future Work
• Strategy Suggestions
2Paul J. Kruzich
®
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
®
• 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
®
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
®
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
®
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
®
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
®
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
®
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
®
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
®
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
®
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
®
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
®
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
®
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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Abuse Liability Guidance - Nonclinical Drug Development

  • 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. ® Presentation Outline—A Nonclinical Perspective • Past Guidance (2010) • Changes with the New Guidance • Implications for Future Work • Strategy Suggestions 2Paul J. Kruzich
  • 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. ® • 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. ® 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. ® 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. ® 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. ® 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. ® 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. ® 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. ® 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. ® 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. ® 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. ® 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. ® 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. ® Assessment of Abuse Potential of Drugs: Guidance for Industry (2017) Paul J. Kruzich, PhD, DSP, DABT Aclairo PDG, Inc. 16Paul J. Kruzich