Clinical Pharmacology Subcommittee (CPSC) Report ACPS Presentation, May 3, 2005 J

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Clinical Pharmacology Subcommittee (CPSC)
ReportACPS Presentation, May 3, 2005Jürgen
Venitz, MD, Ph.D.Goals of the Advisory
SubcommitteeTo provide expertise and feedback
to ACPS, specifically in the areas
ofExposure-Response Modeling
(Pharmacometrics)Pediatric Clinical
PharmacologyPharmacogenetics
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CPSC Meeting, November 3-4, 2004Outline

• Meeting Topics
• CPSC Update
• Pharmacogenetic (PG) Testing of Irinotecan
• Drug-Drug Interaction (DDI) Potential Assessment
• Tribute to Lewis Sheiner, MD
• Biomarkers and Surrogate Markers

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CPSC Meeting, November 3-4, 2004CPCS Update (L.
Lesko, Ph.D., OCPB)

• 1. Identification of Populations at Risk
• Exposure-Response (E/R)
• Modeling and Simulations (M/S)
• Internal use continues to impact drug product
  labeling recommendations
• 2. Utility Functions in Risk Assessment
• No consensus on utility factors/weights
• On hold

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CPSC Meeting, November 3-4, 2004CPCS Update (L.
Lesko, Ph.D., OCPB)

• 3. Pediatric Decision Tree
• Pediatric Database within FDA
• Internal Research Project Ongoing

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CPSC Meeting, November 3-4, 2004CPCS Update (L.
Lesko, Ph.D., OCPB)

• 4. PG Testing for TMPT
• Pediatric Oncology Subcommittee recommended
  labeling language (2003)
• Negotiation with sponsors (6-MP, Azathioprin)
  Ongoing
• 5. DDI Assessment of NMEs
• Including CYP2C8 and CYP2B6
• Guidance Near Completion

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CPSC Meeting, November 3-4, 2004CPCS Update (L.
Lesko, Ph.D., OCPB)

• 6. End-of-Phase 2a Meetings (EOP2a)
• Initiative - Ongoing
• Guidance Under Development
• 7. Assessment of QT-liability
• Internal discussions regarding clinical study
  designs and analyses - Ongoing

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Presentations by
• 1. N.A. Rahman, Ph.D. OCPB
• 2. L. Parodi, MD, Pfizer
• 3. M. Ratain, MD, U of Chicago (Consultant)

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Irinotecan (CPT-11, Camptosar) is an oncological
  agent approved for first- and second-line
  treatment of colorectal cancer
• Major clinical toxicities, limiting its use, are
  neutropenia (infections) and diarrhea
• Complex PK
• CPT-11 forms the active metabolite, SN-38
• SN-38 is further metabolized by UGT1A1 to an
  inactive glucuronide

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• UGT1A1 has various alleles
• for 28, the 7/7 allele (10 prevalence in
  Caucasians) results in reduced glucuronidation
• Other enzymes (CYP3A4, CE) and drug transporters
  (P-gp) are involved in Irinotecan PK as well
  (their significance is unknown)

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Systemic SN-38 exposure is associated with 28
  genotype (7/7 has higher exposures)
• Systemic SN-38 exposure is positively correlated
  with neutropenia
• Relative risk of grade 4 neutropenia 9.3 for 7/7
  genotype
• Diarrhea is less clearly associated with 28
  genotype

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Known Risk Factors for Neutropenia (Label)
• Age
• Prior abdominal/pelvic radiation
• Low performance status
• increased bilirubin (UGT1A1 substrate)
• Proposed Risk Factor
• UGT1A1 Genotype (28, 7/7)

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Current Information across 4 clinical trials
• (Odds Ratio of 7/7 versus 6/6 and 6/7)
• Neutropenia 2.5-16.7
• Diarrhea 0.4-8.4
• Note Studies were not designed to assess the
  strength of association

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Expected UGT1A1 28 PG Test Performance for
  Neutropenia (Pfizer)
• Sensitivity 22 PPV 50
• Specificity 95 NPV 83
• (overall incidence of neutropenia of 20)

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Expected UGT1A1 28 PG Testing Performance for
  Neutropenia (M. Ratain)
• Without PG testing, 100 patients are treated,
  and 10 develop grade 4 neutropenia
• With PG testing, 90 of patient are treated, and
  only 5 develop grade 4 neutropenia
• Test 20 patients to protect 1

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Concerns about PG Testing
• Current clinical studies are limited in assessing
  the strength of association between neutropenia
  and UGT1A128 genotype
• Ongoing clinical trials may identify other PG
  factors of significance
• No validated dosing algorithm after PG testing
  has been established
• Possible loss of efficacy with reduced irinotecan
  doses

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Committee Votes (Yes-No-Abstain)
• 7/7 genotype is associated with a higher risk of
  neutropenia 12-0-0
• 7/7 genotype is associated with a higher risk for
  acute/delayed diarrhea 0-11-1
• 28 PG testing has adequate sensitivity and
  specificity 9-0-3

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CPSC Meeting, November 3-4, 2004PG Testing of
Irinotecan

• Committee Comments
• Lack of optimal dosing regimen even without PG
  testing
• Lower doses may keep patient on regimen
• Additional clinical trial may be need to
  establish a modified dosing regimen
• Serum bilirubin (UGT1A1 substrate) may be safety
  marker

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CPSC Meeting, November 3-4, 2004DDI Potential
Assessment

• Presentations by
• 1. S.-M. Huang , Ph.D., OCPB
• 2. K. Gottesdiener, MD, Merck
• 3. E. LaCluyse, CellzDirect (Consultant)
• 4. K. Reynolds, Pharm.D., OCPB

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CPSC Meeting, November 3-4, 2004DDI Potential
Assessment

• Issues
• FDA is updating DDI guidance for NMEs
• How to integrate in-vitro transporter studies?
• How to integrate in-vitro enzyme induction
  studies?
• Should multiple inhibitor/impairment in-vivo
  studies be required?

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CPSC Meeting, November 3-4, 2004DDI Potential
Assessment

• Committee Votes
• If in-vitro lack of inhibition (CYP1A2, 2C9,
  2C19, 2D6, 3A), no need for in-vivo DDI
  study 12-0-1
• If in-vitro P-gp inhibition, need for in-vivo DDI
  study with P-gp substrate (e.g., digoxin) 8-2-3
• If in-vitro P-gp substrate and 3A4 substrate,
  need for in-vivo DDI study (e.g.,
  ritonavir) 7-4-2

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CPSC Meeting, November 3-4, 2004DDI Potential
Assessment

• Committee Votes (continued)
• If in-vitro P-gp substrate and not 3A4 substrate,
  need for in-vivo DDI study (e.g.,
  verapamil) 6-5-2
• Recommend in-vivo DDI studies for CYP2B6, CYP2B8,
  UGT1A1? 11-0-2
• Recommend in-vivo DDI studies for OATP and MRP
  transporters?
• 3-7-3

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CPSC Meeting, November 3-4, 2004DDI Potential
Assessment

• Committee Votes (continued)
• If in-vitro induction gt40 of positive control,
  need for in-vivo DDI study 3-8-2
• If in-vitro lack of CYP3A4 induction, no need for
  in-vivo DDI studies for CYP3A4, 2C9, 2C19,
  2B6 9-1-3
• Should multiple inhibitor/impairment (in-vivo)
  studies be recommended? 0-12-1

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CPSC Meeting, November 3-4, 2004Tribute to Lewis
Sheiner, MD

• Tribute by T. Blaschke, MD, UCSF
• Lewis Sheiner, MD, UCSF passed away in 2004
• Inaugural member of CPSC (long-term FDA
  consultant)
• Seminal Researcher and Teacher in PK/PD
  (Exposure-Response) and Pharmacometrics
• Learn and Confirm Cycles in Drug Development
  (Empiricism versus Mechanistic Approaches,
  Frequentists versus Bayesians)
• Sheiners Rules

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CPSC Meeting, November 3-4, 2004Biomarkers and
Surrogate Markers

• Presentations by
• 1. J. Woodcock, MD, CDER
• 2. J. Wagner, MD, Ph.D., Merck/PhRMA
• 3. T. Blaschke, MD, Ph.D., UCSF (Consultant)

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CPSC Meeting, November 3-4, 2004Biomarkers and
Surrogate Markers

• Dr Woodcocks comments
• Biomarkers (BM) indicate biological/pathological
  processe(s) and/or pharmacological response(s) to
  therapeutic intervention
• Clinical endpoints (CE) measure how patients
  feel, function or survive
• Surrogate markers (SM) are intended to replace CE
  for efficacy and/or toxicity

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CPSC Meeting, November 3-4, 2004Biomarkers and
Surrogate Markers

• Dr Woodcocks comments (continued)
• Rational use of BM can accelerate drug
  development and decision making
• BM can provide a mechanistic bridge between
  mechanistic preclinical studies and empiric
  clinical testing
• Need business model for (commercial) BM
  development in parallel with drug development

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CPSC Meeting, November 3-4, 2004Biomarkers and
Surrogate Markers

• Dr Woodcocks comments (continued)
• Prentice (statistical) criteria for SM are quite
  strict
• Future CE will not be univariate but rather
  composite endpoints
• Need responder rather than mean analysis from
  pivotal clinical trials, perhaps using BMs
• BMs may help individualize/personalize therapy
  pre- and post-marketing

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CPSC Meeting, November 3-4, 2004Biomarkers and
Surrogate Markers

• Dr. Blaschkes comments
• Reviewed use of BM/SM in HIV/AIDS drug
  development (i.e., CD4 count, HIV viral load)
• SM validation required assays, interventional
  clinical trials and mechanistic models about
  disease progression
• Useful BM need to be causal path BMs, i.e.,
  mechanistic plausible/proximal to disease
  endpoint to provide confirmatory evidence to
  support efficacy

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CPSC Meeting, November 3-4, 2004Biomarkers and
Surrogate Markers

• Dr. Wagners comments (on behalf of PhRMA WG)
• Fit-for-Purpose Qualification of BM
• Exploration (BM as research tool)
• Demonstration (probable/emerging BM)
• Characterization (known/established BM)
• Surrogacy (BM substitutes for CE)

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CPSC Meeting, November 3-4, 2004Biomarkers and
Surrogate Markers

• Dr. Wagners comments (continued)
• Lack of uniform nomenclature
• Need for collaboration between Pharma, FDA, NIH
  and academia for
• decision what BMs to pursue
• decision on what evidence need to accept BM/SM
• Incentives, intellectual property rights, funding