NIH Initiatives in Surrogate Endpoints and Endpoint Analysis

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NIH Initiatives in Surrogate Endpoints and Endpoint Analysis Powered By Docstoc
					         Biomarkers and
       Surrogate Endpoints
NIH Advanced Pharmaceutical Screening Interest Group


                   April 22, 2009
      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
         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
     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
           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
             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
        Conceptual Model
Biomarkers and Surrogate Endpoints
      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
      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
  Biomarkers and Surrogate Endpoints:
   Clinical Research and Applications
               April 1999

• PK/PD Markers
• Biomarkers of Toxicity and Surrogates
  for Safety
      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
   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
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
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)
        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
          Cancer Biomarkers
           http://edrn.nci.nih.gov
• 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
       Osteoarthritis Initiative
http://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
                        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
               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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posted:7/2/2013
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