Nonclinical Studies Subcommittee Advisory Committee for Pharmaceutical Science Introduction

1
Nonclinical Studies SubcommitteeAdvisory
Committee for Pharmaceutical ScienceIntroduction
FDA Objectives Gaithersburg HiltonDecember
14, 1999

• T\NCSS\121499.PPT

2
Nonclinical Studies Subcommittee

• Functions
• To provide advice on improved scientific
  approaches to nonclinical drug development
• A means to foster scientific collaboration among
  FDA, industry, academia, and the public

3
Scientific Advances Opportunities

• Genomics/proteomics
• Information technology
• High throughput technologies
• Mechanistic knowledge
• Cancer, inflammation, cell signalling, etc.
• Artificial intelligence
• Noninvasive imaging

4
An example of accelerating scientific information
and technology

• Safety Assessment

5
Toxicology in the last millennium
B.C. knowledge use of poisons 1500s
Exptl. physiology, toxic vs therapeutic
dose-response (Paracelsus) 1600
Compound microscope 1600-1700 Anatomic
microscopy (Hooke, Malphigi,
van Leeuwenhoek) 1700s Comparative anatomy
(Hunter, Cuvier) Occupational
toxicology (Ramazzini) Environmental cancer
(Potts) 1800s Exptl. physiology toxicolgy
(CO, strychnine, curare) Chemical teratogenesis
(St. Hilare) Cellular pathology (Virchow,
1860s) 1900s Modern regulatory toxicolgy
Cell biochemistry and molecular biology

6
Toxicology in the last half century
1906/1938 Food and Drug Acts first
flight 1940s Chemical carcinogenesis (Millers)
mutagenesis (Auerbach) DNA is the genetic
material 1950 DNA structure Clinical chemistry
(serum biomarkers) Biochemistry (e.g., Krebs
cycle) current approach to systemic toxicity
evaluation 1960 Toxicology as a discipline
(SOT) Thalidomide, teratogensis testing 1970
EPA, OSHA formed man on moon 1970s Genetic
toxicology testing EMS (19070 TSCA
(1978) 1980s Genetic engineering oncogenes
noninvasive imaging 1990s Molecular damage
response and defense Genome sequenced era of
genetic links to disease high-throughput
genetic tools
7
Current Biomarkers of Systemic Toxicity

• Markers of
• Cellular integrity (AST, ALT, etc.)
• Homeostasis (BUN, electrolytes,cell type, etc.)
• Morpohologic evidence of damage
• Host defense responses
• Behavior/appearance/body weight of organism

8
Current approach to safety evaluation

• Clinical Chemistry/Hematology
• Markers of cellular integrity (AST, ALT, etc.)
• Markers of homeostasis (BUN, electolytes, etc.)
• Alterations in circulating cell populations
• Histopathology
• Visible morphologic or staining change
• Host defense cell infiltration
• Behavior/appearance/body weight of organism
• Special tests cancer, mutation, reproduction,
  neurotoxicology, immunotoxicology, etc.

9
Some Opportunities for New/Improved Toxicological
Practices

• Damage-specific responses
• Objective biochemical assays for host-defense
  cell signaling and infiltration
• Better biomarkers of integrity/homeostasis
• e.g., troponins
• Biochemical markers of cell death
• In vivo genetic markers of mutational damage,
  oncogene activation, and suppressor inactivation
• Noninvasive technologies
• Humanized and/or transgenic animals
• Cell culture microengineering

10
Molecular Evolution of Defense Systems

• Systems have evolved to protect and repair each
  major function
• Defense systems are often inducible
• Molecules often evolve from function to repair
• Key defense systems are conserved
• Understanding these systems will provide the next
  generation of surrogate biomarkers for monitoring
  damage to cells and tissues

11
(No Transcript)
12
Some Damage- or Agent-Inducible Genes
Damage
Type Functional Class /Inducer Class
Example Genes Protein structure
Protein denaturation HSP70, clpB DNA integrity
DNA damage dinD,
recA, GADD153 Oxidative Protectants Redox
balance katG, soi28, GST Growth
Control Cell proliferators
FOS, JUN DNA
damage Metal Inducible Toxic metals
merR Xenobiotic Inducible
Xenobiotics CYP1A1, CYP2E1
13
DNA Microarray or Gene Chip with Multiple Probes
Containing scores of potential biomarkers, e.g.
DNA damage-response genes Protein damage-response
genes Intracellular free radical-response genes
14
Genomics to Proteomics
Sample mixed with Ab-coated spheres and labeled Ab
Biomarker proteins are in patient serum sample
Microsphere color identifies the protein
captured Intensity of tagged Ab reflects amount
of captured protein
15
What do we need to know?

• Relationship of endpoint to health
• Relationship to outcomes in established assays
• Relationship between laboratory models and man
• Reproducibility, accuracy, sensitivity, robustness

16
Application of Safety Biomarkers to Human Studies

• Secreted proteins that are upregulated following
  toxic insult
• Tissue/organ-specific proteins that signal loss
  of cellular integrity
• Inaccessible upregulated membrane proteins that
  bind specific non-invasively monitorable probes

17
Biochemical Markers of Pathology

• Damage/Insult Defense Response
• Cell death Caspase-mediated cell death
• Cell death/tissue damage Chemokine/cytokine-medi
  ated
• inflammatory response
• Foreign/damaged protein Immune responses/NK
  receptor

18
(No Transcript)
19
Better biomarkers of cell integrity and
homeostasis
20
Control
Doxorubicin
Immunofluorescent Labeling of Cardiac Troponin I
(cTnI) in Doxorubicin-induced Cardiomyopathy
Intercalated disks (arrow), I-bands (circle), and
staining intensity (box) are reduced, while
vacuoles (triangle) are increased in DXR-
treated animals.
21
Effect of Doxorubicin (DXR)on Serum Cardiac
Troponin T (TnT)
Serum Cardiac TnT (ng/kg)

• Cumulative Dose DXR (mg/kg)

22
Influence of the Severity of Doxorubicin Induced
Cardiomyopathy of the Concentration of Serum
Cardiac Troponin T (TnT)
Serum Cardiac TnT Concentration (ng/ml)

• Cardiomyopathy Score

23
How to focus resources among opportunities?

• ACPS Nonclinical Studies Subcommittee
• Identify and recommend focus areas
• Identify experts in focus areas form expert
  working groups (EWGs) with nominations from
• Federal Register announcements (Public)
• FDA and Stakeholders (Collaborators)
• Professional Societies
• Steering committee to collaborative projects
• Support workshops and facilitate reports

24
Potential collaborators

• FDA
• CDER
• CBER
• Industry
• PhRMA
• BIO
• Academia
• Public Institutions

25
Objectives

• 1. To recommend approaches and mechanisms to
  improve
• Nonclinical information for effective drug
  development
• Predictivity of nonclinical tests for human
  outcomes
• Linkage between nonclinical and clinical studies
  
• and
• 2. To facilitate collaborative approaches to
  advancing the scientific basis of drug
  development and regulation

26
History and Next Steps

• NCSS Subcommittee meeting 8/31/99
• Define objectives and operating principles
• Define focus areas
• Discuss initial focus areas and mechanisms for
  implementation
• Define operating structure
• ACPS meeting 9/24/99
• ACPS endorsed concept
• Select initial focus areas
• Form EWGs
• EWGs identify collaborators and identify resources