Nonclinical Studies SubcommitteeAdvisory Committee for Pharmaceutical

Science

Introduction & FDA Objectives

Gaithersburg HiltonDecember 14, 1999

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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

Scientific Advances & Opportunities

Genomics/proteomics Information technology High throughput technologies Mechanistic knowledge

Cancer, inflammation, cell signalling, etc. Artificial intelligence Noninvasive imaging

An example of accelerating scientific information and technology:

Safety Assessment

Toxicology in the last millennium~~ B.C. knowledge & use of poisons

1500’s Exptl. physiology, toxic vs therapeutic dose-response (Paracelsus)

1600 Compound microscope1600-1700 Anatomic microscopy (Hooke, Malphigi, van Leeuwenhoek)

1700’s Comparative anatomy (Hunter, Cuvier); Occupational toxicology (Ramazzini); Environmental cancer (Potts)

1800’s Exptl. physiology & toxicolgy (CO, strychnine, curare)Chemical teratogenesis (St. Hilare) Cellular pathology (Virchow, 1860’s)

1900’s Modern regulatory toxicolgy Cell biochemistry and molecular biology

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 tosystemic toxicity evaluation

1960 Toxicology as a discipline (SOT)Thalidomide, teratogensis testing

1970 EPA, OSHA formed; man on moon1970’s Genetic toxicology testing; EMS (19070; TSCA (1978)

1980’s Genetic engineering; oncogenes; noninvasive imaging

1990’s Molecular damage response and defense Genome sequenced; era of genetic links to disease; high-throughput genetic tools

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

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.

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

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

Some Damage- or Agent-Inducible Genes

Damage TypeFunctional Class /Inducer Class Example GenesProtein structure Protein denaturation HSP70, clpBDNA integrity DNA damage dinD, recA, GADD153Oxidative Protectants Redox balance katG, soi28, GSTGrowth Control Cell proliferators FOS, JUN DNA damage Metal Inducible Toxic metals merRXenobiotic Inducible Xenobiotics CYP1A1, CYP2E1

DNA damage-response genes

Protein damage-response genes

Intracellular free radical-response genes

DNA Microarray or “Gene Chip” with Multiple Probes

Containing scores of potential biomarkers, e.g.

Genomics to Proteomics

Microsphere color identifies the protein capturedIntensity of tagged Ab reflects amount of captured protein

Sample mixed with Ab-coated spheres and labeled Ab

Biomarker proteins are in patient serum sample

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

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

Biochemical Markers of Pathology

Damage/Insult Defense ResponseCell death Caspase-mediated cell deathCell death/tissue damage Chemokine/cytokine-mediated

inflammatory responseForeign/damaged protein Immune responses/NK receptor

Better biomarkers of cell integrity and homeostasis

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.

Control Doxorubicin

Effect of Doxorubicin (DXR)Effect of Doxorubicin (DXR)on Serum Cardiac Troponin T (TnT)on Serum Cardiac Troponin T (TnT)

Cumulative Dose DXR (mg/kg)

Seru

m C

ardi

ac T

nT(n

g/kg

)

Influence of the Severity of Doxorubicin Induced Influence of the Severity of Doxorubicin Induced Cardiomyopathy of the Concentration of Serum Cardiomyopathy of the Concentration of Serum

Cardiac Troponin T (TnT)Cardiac Troponin T (TnT)

Cardiomyopathy Score

Ser

um C

ardi

ac T

nTC

once

ntra

tion

(ng/

ml)

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

Potential collaborators

FDA CDER CBER

Industry PhRMA BIO

Academia Public Institutions

Objectives1. 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 and2. To facilitate collaborative approaches to

advancing the scientific basis of drug development and regulation

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