Understand Translational Research Tools

Overview

Your patient group can help accelerate the discovery stage of therapy development for your disease by working with patients, scientists, and industry partners to develop translational research tools. Translational research and development is the process of turning observations from the laboratory, clinic, and patient community into therapies that improve the health of the patients. Translational research tools are needed to bridge the gap from understanding the disease process to identifying therapeutic targets and testing potential therapies in preparation for clinical research in humans. These tools include biological assays (bioassays), biomarkers, cell and animal models, and biorepositories.

Bioassays

In the context of medical research, a biological assay (bioassay) is a procedure that allows a biological process to be quantified.  Bioassays are important in the development of drugs and many biologics.

  • In early therapy development, bioassays help determine which potential compounds have a higher likelihood of being an effective treatment.
  • Bioassays can be cell-free (or biochemical) or cell-based procedures.
  • High-throughput assays (also called high-throughput screenings) utilize advanced technology to miniaturize and automate the bioassay so that large libraries of potential therapies can be screened very quickly. For example, the National Center for Advancing Translational Sciences (NCATS) qHTS can screen more than a million compounds a day.
  • Bioassay procedures usually include applying a set of reagents. A reagent is a substance or compound added to a system to cause a chemical reaction or added to test whether a reaction occurs. 
  • The set of reagents used in a bioassay produces a detectable signal that can quantify the target biological activity. Signals that can be measured quantitatively include:
    • Absorbance
    • Fluorescence
    • Luminescence
    • Radioactivity
  • Required qualities of bioassays include:  
    • Reproducibility
    • Reliability
    • Robust
    • Biologically relevant
  • Knowing the biological pathway underlying your disease can help researchers develop a more comprehensive bioassay.
  • Researcher(s) developing bioassays for your disease may benefit from knowing about NCATS Assay Guidance Manual, a free, best-practices online resource that is devoted to the successful development of robust, early-stage therapy discovery assays.

Biomarkers

Biological markers (biomarkers) are characteristics that can be objectively measured and used as an indicator of normal biological processes, disease processes, or pharmacologic responses to a therapy. Biomarkers are important for the development of drugs, biologics, and certain medical devices.

  • Biomarkers are a subcategory of medical signs and can be detected through different tests and procedures. Examples of biomarkers include:
    • Blood pressure and body temperature (physiological biomarkers).
    • LDL cholesterol level and red blood cell count (molecular biomarkers).
    • Tumor detected by contrast MRI or bone fracture detected by X-ray (imaging biomarkers).
  • Biomarkers can also be categorized by what they measure. The biomarkers that are important to the therapy development process include:
    • Susceptibility/risk biomarkers
      • Associated with an  increased or decreased chance of developing a disease or medical condition.
      • Identifies patients who do not yet clinically have the disease, which is important when the treatment will be most effective prior to development of symptoms.
    • Diagnostic biomarkers
      • Confirms or establishes diagnosis.
      • Selects patient population for clinical trials.
    • Monitoring biomarker
      • Detects the change in degree or extent of disease.
      • Indicates toxicity or assesses safety.
      • Provides evidence of exposure.
    • Prognostic biomarker
      • Identifies the likelihood of a clinical event, disease recurrence, or progression in patients diagnosed with the disease.
      • Enriches clinical trials with patients who have a higher likelihood of experiencing an event and therefore increase statistical power.
    • Predictive biomarker
      • Indicates the likely benefit to the patient from the treatment, compared with their condition at baseline. 
      • Classifies patients into responders and non-responders for the therapeutic agent using companion diagnostics (a test or assay that detects a predictive biomarker).
      • Enriches later phases of clinical trials with patients more likely to respond to the therapeutic agent.
      • Is usually specific to a therapeutic agent.
      • Does not guarantee benefit, but rather excludes patients who are most likely not to benefit.
    • Pharmacodynamic (response) biomarker
      • Shows biological response related to a therapy or environmental exposure.
      • May act as a surrogate clinical endpoint (also known as efficacy response biomarker) in a clinical trial when validated. For a biomarker to be validated, it: 
        • Must be solid scientific evidence that a biomarker consistently and accurately predicts a clinical outcome, either a benefit or harm.
        • Is important if survival or recurrence is the clinical outcome endpoint.
      • Validated surrogate clinical endpoint biomarkers may
        • Provide early evidence about the safety and efficacy of a therapy.
        • Reduce the risk of harm to subjects; the early data provided by biomarkers can allow researchers the opportunity to stop administration of a therapy potentially harmful to subjects before the associated clinical data would be available.
        • Provide useful information for patient management, for example, whether to continue treatment or to adjust dose.
        • Allow researchers to design smaller, more efficient studies, reducing the number of subjects exposed to a given experimental therapy.
        • Speed the overall therapy development process, allowing effective treatments to reach their target patient populations sooner.
      • Until validated, a biomarker can still be considered by the U.S. Food and Drug Administration (FDA) in the marketing review process of the potential therapy as “reasonably likely surrogate endpoint” or “candidate surrogate endpoint.”
    • Safety biomarker
      • Monitors adverse effects of the therapy.
  • CDER Biomarker Qualification Program (2018) provides more information about biomarkers and their use in clinical trials, as well as steps to have a biomarker qualified by the FDA. 
    • Qualification means the biomarker has undergone a formal regulatory process to ensure that the FDA can rely on it to have a specific interpretation and application in therapy development and marketing review process, within the stated context of use.
  • Other resources include:
    • BEST (Biomarkers, EndpointS, and other Tools) Resource (2018) is a glossary that clarifies definitions of different types of biomarkers and clinical assessments. This glossary describes the roles of biomarkers in research and therapy development and was developed by the FDA-NIH Biomarker Working Group
    • Developing and Validating Biomarkers (2016) is a video presentation from a Global Genes Rare Advocacy Summit that outlines the role of patient advocacy organizations in the development of biomarkers. The 1 hour presentation:
      • Defines biomarkers and different types.
      • Discusses how they can be used in research.
      • Includes specific examples of the use of biomarkers in accelerating diagnosis and treatment of rare diseases.

Cell and Animal Models

A disease model is an animal or cell which displays all or some of the disease processes that are observed in the actual human. 

  • Studying disease models aids understanding of how the disease develops and testing potential treatment approaches.
  • Preclinical studies in animal or cell models demonstrating the safety and efficacy of a potential treatment must be submitted to the FDA prior to being granted approval for trials in humans.
  • Cell and animal models include:
    • Primary or patient-derived immortalized cell lines.
    • Patient-derived induced pluripotent stem cell (iPSCs).
    • Organoids, which are tiny, self-organized, three-dimensional tissue cultures that are derived from stem cells. Such cultures can be crafted to replicate much of the complexity of an organ, or to express selected aspects of it like producing only certain types of cells.
    • Yeast.
    • Slime mold.
    • Roundworm.
    • Fruit fly.
    • Zebra fish.
    • Frog.
    • Mouse. 
    • Rat.
    • Rabbit.
    • Pig.
    • Other mammals.
  • Animal Model Qualification Program provides information about the steps to have an animal model qualified by the FDA for preclinical studies.

Biorepository

A biorepository or biobank is fundamentally a library that stores and manages biological samples, known as biospecimens, for use in research. Your group can lead the effort to establish a biorepository for your disease(s).

  • A biorepository can accelerate the development of new therapies by providing researchers with biospecimens to:
    • Improve understanding of the underlying disease process.
    • Examine gene expression at different ages, disease stages, or tissue types.
    • Predict toxicity of potential treatment in tissue samples.
    • Identify and clarify biomarkers.
    • Aid in the selection of preclinical cellular and/or animal models.
  • Biosamples may include:
    • Tissue
    • Blood
    • Saliva
    • Plasma
    • Purified DNA
    • Urine
  • Donors to the biorepository may include:
    • Patients.
    • Siblings who do not have the disease.
    • Parents or other close relatives, depending on disease family pattern.
  • Timing of the collection of samples will depend on the disease, samples being collected, and end goal of bioregistry. 
    • During patient lifetime:
      • During surgical procedures or tests.
      • At the time a patient joins biobank. 
      • Specific times throughout the course of disease.
    • At time of patient’s death:
      • Although possibly a very sensitive topic while a patient, especially when the patient is a child living with a currently fatal disease, you may wish to educate patients (if old enough) or parents about providing samples to the biobank before the end stage of disease so arrangements can be made ahead of time. 
  • Donor (patient) information, such as data about their medical condition and demographic characteristics, is usually collected along with samples.
    • Often collected in conjunction with a natural history study.
    • Personal Identifying Information (PII) should be protected through de-identification coding of samples and donor data.
  • Informed consent processes should be in place for donors.
  • Current best practices should be used to collect, maintain, and share the highest quality biospecimens.
  • Long term financial burden of maintaining biorepository should be considered prior to beginning the process.
  • Researchers applying for use of specimens from biorepository should have Institutional Review Board (IRB) approval for their research study.
  • Prior to developing a biorepository, make sure one does not already exist for your disease(s).
  • Check with the NIH Institute or Center (IC) most closely aligned with your disease to determine whether there are any grant opportunities or programs to start a biorepository.
  • Learn more about biorepositories using the following resources:

Resources

Bioassays
Assay Guidance Manual National Center for Advancing Translational Sciences (NCATS) (link)
Biomarkers
CDER Biomarker Qualification Program U.S. Food and Drug Administration (FDA) (link)
Cell and Animal Models
Animal Model Qualification Program U.S. Food and Drug Administration (FDA) (link)
Biorepository
NCI Best Practices for Biospecimen Resources National Cancer Institute (NCI) (link)

Your patient group can help accelerate the discovery stage of therapy development for your disease by working with patients, scientists, and industry partners to develop translational research tools. Translational research and development is the process of turning observations from the laboratory, clinic, and patient community into therapies that improve the health of the patients. Translational research tools are needed to bridge the gap from understanding the disease process to identifying therapeutic targets and testing potential therapies in preparation for clinical research in humans. These tools include biological assays (bioassays), biomarkers, cell and animal models, and biorepositories.

In the context of medical research, a biological assay (bioassay) is a procedure that allows a biological process to be quantified.  Bioassays are important in the development of drugs and many biologics.

  • In early therapy development, bioassays help determine which potential compounds have a higher likelihood of being an effective treatment.
  • Bioassays can be cell-free (or biochemical) or cell-based procedures.
  • High-throughput assays (also called high-throughput screenings) utilize advanced technology to miniaturize and automate the bioassay so that large libraries of potential therapies can be screened very quickly. For example, the National Center for Advancing Translational Sciences (NCATS) qHTS can screen more than a million compounds a day.
  • Bioassay procedures usually include applying a set of reagents. A reagent is a substance or compound added to a system to cause a chemical reaction or added to test whether a reaction occurs. 
  • The set of reagents used in a bioassay produces a detectable signal that can quantify the target biological activity. Signals that can be measured quantitatively include:
    • Absorbance
    • Fluorescence
    • Luminescence
    • Radioactivity
  • Required qualities of bioassays include:  
    • Reproducibility
    • Reliability
    • Robust
    • Biologically relevant
  • Knowing the biological pathway underlying your disease can help researchers develop a more comprehensive bioassay.
  • Researcher(s) developing bioassays for your disease may benefit from knowing about NCATS Assay Guidance Manual, a free, best-practices online resource that is devoted to the successful development of robust, early-stage therapy discovery assays.

Biological markers (biomarkers) are characteristics that can be objectively measured and used as an indicator of normal biological processes, disease processes, or pharmacologic responses to a therapy. Biomarkers are important for the development of drugs, biologics, and certain medical devices.

  • Biomarkers are a subcategory of medical signs and can be detected through different tests and procedures. Examples of biomarkers include:
    • Blood pressure and body temperature (physiological biomarkers).
    • LDL cholesterol level and red blood cell count (molecular biomarkers).
    • Tumor detected by contrast MRI or bone fracture detected by X-ray (imaging biomarkers).
  • Biomarkers can also be categorized by what they measure. The biomarkers that are important to the therapy development process include:
    • Susceptibility/risk biomarkers
      • Associated with an  increased or decreased chance of developing a disease or medical condition.
      • Identifies patients who do not yet clinically have the disease, which is important when the treatment will be most effective prior to development of symptoms.
    • Diagnostic biomarkers
      • Confirms or establishes diagnosis.
      • Selects patient population for clinical trials.
    • Monitoring biomarker
      • Detects the change in degree or extent of disease.
      • Indicates toxicity or assesses safety.
      • Provides evidence of exposure.
    • Prognostic biomarker
      • Identifies the likelihood of a clinical event, disease recurrence, or progression in patients diagnosed with the disease.
      • Enriches clinical trials with patients who have a higher likelihood of experiencing an event and therefore increase statistical power.
    • Predictive biomarker
      • Indicates the likely benefit to the patient from the treatment, compared with their condition at baseline. 
      • Classifies patients into responders and non-responders for the therapeutic agent using companion diagnostics (a test or assay that detects a predictive biomarker).
      • Enriches later phases of clinical trials with patients more likely to respond to the therapeutic agent.
      • Is usually specific to a therapeutic agent.
      • Does not guarantee benefit, but rather excludes patients who are most likely not to benefit.
    • Pharmacodynamic (response) biomarker
      • Shows biological response related to a therapy or environmental exposure.
      • May act as a surrogate clinical endpoint (also known as efficacy response biomarker) in a clinical trial when validated. For a biomarker to be validated, it: 
        • Must be solid scientific evidence that a biomarker consistently and accurately predicts a clinical outcome, either a benefit or harm.
        • Is important if survival or recurrence is the clinical outcome endpoint.
      • Validated surrogate clinical endpoint biomarkers may
        • Provide early evidence about the safety and efficacy of a therapy.
        • Reduce the risk of harm to subjects; the early data provided by biomarkers can allow researchers the opportunity to stop administration of a therapy potentially harmful to subjects before the associated clinical data would be available.
        • Provide useful information for patient management, for example, whether to continue treatment or to adjust dose.
        • Allow researchers to design smaller, more efficient studies, reducing the number of subjects exposed to a given experimental therapy.
        • Speed the overall therapy development process, allowing effective treatments to reach their target patient populations sooner.
      • Until validated, a biomarker can still be considered by the U.S. Food and Drug Administration (FDA) in the marketing review process of the potential therapy as “reasonably likely surrogate endpoint” or “candidate surrogate endpoint.”
    • Safety biomarker
      • Monitors adverse effects of the therapy.
  • CDER Biomarker Qualification Program (2018) provides more information about biomarkers and their use in clinical trials, as well as steps to have a biomarker qualified by the FDA. 
    • Qualification means the biomarker has undergone a formal regulatory process to ensure that the FDA can rely on it to have a specific interpretation and application in therapy development and marketing review process, within the stated context of use.
  • Other resources include:
    • BEST (Biomarkers, EndpointS, and other Tools) Resource (2018) is a glossary that clarifies definitions of different types of biomarkers and clinical assessments. This glossary describes the roles of biomarkers in research and therapy development and was developed by the FDA-NIH Biomarker Working Group
    • Developing and Validating Biomarkers (2016) is a video presentation from a Global Genes Rare Advocacy Summit that outlines the role of patient advocacy organizations in the development of biomarkers. The 1 hour presentation:
      • Defines biomarkers and different types.
      • Discusses how they can be used in research.
      • Includes specific examples of the use of biomarkers in accelerating diagnosis and treatment of rare diseases.

A disease model is an animal or cell which displays all or some of the disease processes that are observed in the actual human. 

  • Studying disease models aids understanding of how the disease develops and testing potential treatment approaches.
  • Preclinical studies in animal or cell models demonstrating the safety and efficacy of a potential treatment must be submitted to the FDA prior to being granted approval for trials in humans.
  • Cell and animal models include:
    • Primary or patient-derived immortalized cell lines.
    • Patient-derived induced pluripotent stem cell (iPSCs).
    • Organoids, which are tiny, self-organized, three-dimensional tissue cultures that are derived from stem cells. Such cultures can be crafted to replicate much of the complexity of an organ, or to express selected aspects of it like producing only certain types of cells.
    • Yeast.
    • Slime mold.
    • Roundworm.
    • Fruit fly.
    • Zebra fish.
    • Frog.
    • Mouse. 
    • Rat.
    • Rabbit.
    • Pig.
    • Other mammals.
  • Animal Model Qualification Program provides information about the steps to have an animal model qualified by the FDA for preclinical studies.

A biorepository or biobank is fundamentally a library that stores and manages biological samples, known as biospecimens, for use in research. Your group can lead the effort to establish a biorepository for your disease(s).

  • A biorepository can accelerate the development of new therapies by providing researchers with biospecimens to:
    • Improve understanding of the underlying disease process.
    • Examine gene expression at different ages, disease stages, or tissue types.
    • Predict toxicity of potential treatment in tissue samples.
    • Identify and clarify biomarkers.
    • Aid in the selection of preclinical cellular and/or animal models.
  • Biosamples may include:
    • Tissue
    • Blood
    • Saliva
    • Plasma
    • Purified DNA
    • Urine
  • Donors to the biorepository may include:
    • Patients.
    • Siblings who do not have the disease.
    • Parents or other close relatives, depending on disease family pattern.
  • Timing of the collection of samples will depend on the disease, samples being collected, and end goal of bioregistry. 
    • During patient lifetime:
      • During surgical procedures or tests.
      • At the time a patient joins biobank. 
      • Specific times throughout the course of disease.
    • At time of patient’s death:
      • Although possibly a very sensitive topic while a patient, especially when the patient is a child living with a currently fatal disease, you may wish to educate patients (if old enough) or parents about providing samples to the biobank before the end stage of disease so arrangements can be made ahead of time. 
  • Donor (patient) information, such as data about their medical condition and demographic characteristics, is usually collected along with samples.
    • Often collected in conjunction with a natural history study.
    • Personal Identifying Information (PII) should be protected through de-identification coding of samples and donor data.
  • Informed consent processes should be in place for donors.
  • Current best practices should be used to collect, maintain, and share the highest quality biospecimens.
  • Long term financial burden of maintaining biorepository should be considered prior to beginning the process.
  • Researchers applying for use of specimens from biorepository should have Institutional Review Board (IRB) approval for their research study.
  • Prior to developing a biorepository, make sure one does not already exist for your disease(s).
  • Check with the NIH Institute or Center (IC) most closely aligned with your disease to determine whether there are any grant opportunities or programs to start a biorepository.
  • Learn more about biorepositories using the following resources:

Resources

Bioassays
Assay Guidance Manual National Center for Advancing Translational Sciences (NCATS) (link)
Biomarkers
CDER Biomarker Qualification Program U.S. Food and Drug Administration (FDA) (link)
Cell and Animal Models
Animal Model Qualification Program U.S. Food and Drug Administration (FDA) (link)
Biorepository
NCI Best Practices for Biospecimen Resources National Cancer Institute (NCI) (link)