T0 Phase of Translational Research

Lecture Overview

  • Presented by Dr. Jeff Harrison
  • Focus: T0 Phase of Translational Research

Lecture Objectives

  • Define Therapeutic Modalities: Understand different types of interventions aimed at treating diseases.
  • Describe Therapeutic Modalities: Discuss small molecules, biologics, drugs, devices, and diagnostics used in translational research.
  • Preclinical Model Systems: Explore how these systems simulate molecular, cellular, and physiological disease aspects in humans.
  • Benchmark Findings: Identify essential results necessary to progress from preclinical studies to first-in-human clinical trials.

Outline of the Lecture

  1. T0 Phase Objectives in Translational Research Phases
  2. Therapeutic Modalities in Translational Research
    • Drugs
    • Devices
    • Diagnostics
  3. Preclinical Approaches
  4. Expectations and Milestones
    • Moving from T0 to T1 Phase
  5. Rigor and Reproducibility in Preclinical Research

Phases of Translational Research

  • Labels: T0, T1, T2, T3, T4
  • T0 Phase:
    • Basic and applied scientific research
    • Focus on defining mechanisms, discovering drug targets, and conducting preclinical studies.

Goals of T0 Research

  • Identify Functional Significance: Study genetic polymorphisms and their relevance to diseases.
  • Mechanisms of Disease: Investigate processes behind disease initiation and progression.
  • Human Tissue Collection: Gather samples from both diseased and healthy subjects to inform clinical studies.
  • Development of Therapeutics: Create new drug candidates including small molecules and biologics.
  • Novel Diagnostics and Devices: Innovate testing methods and medical devices.

Preclinical Studies and Methods

  • Main focus on T0 phase research.
  • Typically involve animal models but can also include human blood, human cell lines, and computational models (in silico methodologies).
  • Bench Research: This term encapsulates T0 phase studies aimed at ushering in first human studies (T1 Phase).

Therapeutic Modalities

  • Defined as interventions used to heal individuals, categorized into:
    • Drugs: Small Molecules and Biologics
    • Devices
    • Diagnostics

Definition of a Drug (FDA Guidance)

  • Recognized by an official pharmacopoeia or formulary.
  • Used for diagnosis, treatment, cure, or prevention of disease.
  • Distinct from food, affecting cell/organ function/structure.
  • Cannot be a component or accessory of a device.

Drugs:

Small Molecules
  • Characteristics:
    • Typically limited to a molecular weight of 900 daltons with a preference below 500 daltons for ease of formulation and absorption.
    • Good oral bioavailability; ability to cross biological membranes.
  • Examples:
    • Acetaminophen: Simple organic structure, widely used pain reliever and fever reducer.
    • Morphine: More complex, used in pain management.
    • Cyclosporine: A larger yet still well-defined chemical used primarily in organ transplant cases to prevent rejection.
Biologic Drugs
  • Characteristics:
    • Diverse range: vaccines, blood products, cells, gene therapies, and recombinant proteins.
    • Often derived from natural sources or produced using biotechnological methods.
  • Examples:
    • Monoclonal Antibodies: Used in blocking agents such as those targeting tumor necrosis factor alpha.
    • Variants include fully humanized or chimeric
    • Etanercept: Fusion protein consisting of the extracellular domain of TNF receptor fused to human IgG1.
    • CAR T Cell Therapies: Adoptive cellular approaches for cancer treatment.
    • Gene Therapy: Techniques aiming to modify or manipulate genes to treat conditions.
Interest in Drug Development
  • Notable sales from biologic agents, e.g., adalimumab, etanercept, and infliximab were leading drugs in 2016.
  • Importance in therapeutic development highlighted by market potential and sales figures.

Medical Devices

  • Definition:
    • Instruments, apparatuses, machines, or implants used for diagnosing or treating diseases without exerting chemical action.
    • Can be used in humans and animals (veterinary medicine included).

Distinctions Between Devices and Drugs

  • Therapeutic Effect: Devices achieve effects through physical changes rather than chemical action.
  • Metabolism Dependency: Devices are typically not metabolized for their intended purpose.

Examples of Medical Devices

  • Simple Devices: Band-aids, thermometers, tongue depressors
  • Moderately Complex Devices: Insulin pumps, surgical drapes
  • Complex Devices: Pacemakers, defibrillators, joint implants (e.g., knee replacements)

FDA Classification of Devices

  • Class I: Minimal regulatory controls; examples include bandages and exam gloves.
  • Class II: Require additional controls; examples include acupuncture needles and wheelchairs.
  • Class III: Require pre-market approval (PMA) with substantial clinical data; examples include pacemakers and defibrillators.

FDA Approval Process

  • Class I & II: Pre-market notification proving safety/effectiveness is essential, but extensive human clinical data is not needed.
  • Class III: More demanding, requiring substantial laboratory and clinical evidence for licensing, thus extending development timelines and cost.

Conclusion

  • The T0 phase is foundational in translational research, encompassing the early stages of drug discovery and assessment, involving multiple modalities to approach disease treatment and prevention.