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Presented by Gregory Downing, Ph.D. at the Nonclinical Studies Subcommittee of the Advisory Committee for Pharmaceutica

Presented by Gregory Downing, Ph.D. at the Nonclinical Studies Subcommittee of the Advisory Committee for Pharmaceutical Science March 9, 2000. NIH Research Activities - Biomarkers and Surrogate Endpoints. BIOMARKERS NIH RESEARCH INTERESTS. Emerging bottlenecks in drug discovery

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Presented by Gregory Downing, Ph.D. at the Nonclinical Studies Subcommittee of the Advisory Committee for Pharmaceutica

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  1. Presented by Gregory Downing, Ph.D. at the Nonclinical Studies Subcommittee of the Advisory Committee for Pharmaceutical Science March 9, 2000

  2. NIH Research Activities -Biomarkers and Surrogate Endpoints

  3. BIOMARKERS NIH RESEARCH INTERESTS • Emerging bottlenecks in drug discovery • genomics, combinatorial chemistry, high throughput screening technologies • Improve efficiency of clinical trials • Speed translation of basic science • New challenges • chemoprevention, gene therapy, vaccines • Public health issue

  4. NIH INITIATIVES • May 1997 Pharmaceutical industry meeting • November 1997 Clinical Trials: Looking to the Future • May 1998 Biomarkers Issues Identification Meeting • July 1998 Definitions Working Group • April - September 1998 Informational Meetings with Academic Centers Research and Pharmaceutical Industry

  5. NIH INITIATIVES (cont.) • September 1998 - March 1998 • Disease Specific Roundtable Discussions • December 1998 - Clinical Trial Design and Biostatistics Workshop • April 1999 - Multidisciplinary Conference http://biomarkers.od.nih.gov • Specific Initiatives • NIEHS Markers Meeting November 1999

  6. DEFINITIONS Biological Marker (Biomarker) - A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarker Definitions Working Group - 1998

  7. DEFINITIONS Clinical Endpoint - A characteristic or variable that reflects how a patient feels, functions or survives. Surrogate Endpoint - a biomarker intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence. Biomarkers Definition Working Group -1998

  8. Conceptual Model Biomarkers and Surrogate Endpoints

  9. USES OF BIOMARKERS • PRE-DEVELOPMENT STUDIES • Correlate with diagnosis and prognosis • Investigate pathophysiologic mechanisms • PRE-CLINICAL STUDIES • Confirm activity IN VIVO • Explore concentration-response relationships • PHASE I-II CLINICAL STUDIES • Evaluate activity • Develop dose-response relationships

  10. USES OF BIOMARKERS • PHASE III CLINICAL STUDIES • Stratifying study populations • Conducting interim analysis of efficacy/safety • Applied toward regulatory approval • CLINICAL PRACTICE • Establish diagnosis • Monitor treatment response • Use as prognostic or predictive measure

  11. Biomarkers and Surrogate Endpoints:Clinical Research and ApplicationsApril 1999 • PK/PD Markers • Biomarkers of Toxicity and Surrogates for Safety

  12. KEY RESEARCH GAPS • Lack of full utilization of available toxicity markers • “Awareness gap” - emphasize need for improved measures of safety biomarkers • Need to develop data associating particular genes/proteins/small molecules to human pathology • Coordinated effort to relate animal toxicity markers to human responses • Need for key organ system toxicity markers

  13. BEST OPPORTUNITIES FOR DEVELOPING TOXICITY MARKERS • Relate alterations in signal transduction and other pathways to clinical toxicology of particular agents • Define genes related to human toxicology • Development of HTS to correlate gene expression with protein expression as they relate to toxicological responses to drugs

  14. USE OF EMERGING TECHNOLOGIES • Develop and apply analytical tools to discover small molecular markers to assess drug toxicity • Utilize imaging technologies to understand toxicology mechanisms at the molecular, whole organ, and whole body level • Expand application of cDNA array technologies and proteomics • Clinical technologies – less invasive tools • Use of humanized transgenic animal models to evaluate ADME and molecular/tissue/organ specific toxicity

  15. Research Infrastructure Needs • Stimulate collaboration among sectors of the biomedical research enterprise to develop and evaluate toxicity markers • Establish a consortium of public and private institutions • Utilize funding strategies and networks for marker evaluation (similar to NCI)

  16. NIH Research Initiatives • Cancer Biomarkers Research Laboratories • PET ligands for neuroimaging • Pharmacogenomics • Neuroinformatics initiative (NIFTI) • Osteoarthritis Initiative • Diabetes markers • Imaging programs for urologic disorders • Immunomodulatory markers • Cardiovascular markers • Hematologic disorders • Toxicity markers • Chronic lung diseases

  17. An infrastructure for supporting collaborative research on molecular, genetic and other biomarkers in early cancer detection and risk assessment. Discovery, technology development, clinical validation 17 development labs, 6 validation labs, 12 clinical/epidemiology centers Ovarian, prostate, lung, liver, colon, breast Cancer Biomarkers http://edrn.nci.nih.gov

  18. Osteoarthritis Initiativehttp://www.nih.gov/niams/news/oisg/index.htm • Identify and evaluate biomarkers as candidates for OA surrogate endpoints • Prospective natural history cohorts • Public-private partnerships • Evaluate: • Biochemical markers • Structural markers - (radiographs, MRI, OCT) • Genetic markers

  19. Next Steps • Organization of Information (Bioinformatics) • Nosology, classification, characterizing disease course • Establish/maintain biomarker electronic catalogues • Improve linkage of biomarkers to clinical information • Establishment of web based knowledge centers • Categories: • Disease • Technology • Cell/Tissue/Organ • Name of marker (protein, antibody, gene, etc.) • Others • Issues: Access to data, identifying data sources

  20. Next Steps • Research resources • Specimen and image repositories • Assay validation laboratories • Comparison of biomarkers (cross-validation) • Epidemiologic/longitudinal disease cohorts • Expand/extend laboratory technologies to clinical measures (accuracy and precision) • Technical expertise • Expand clinical research capacity • Integrate new disciplines

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