IGNITE - Definitions for Key Terms

External Validity

External validity is the extent to which results of a study can be generalized from one setting to anothe

There are different types of external validity, including:

  • Face Validity: The similarity between the model and the clinical manifestation of the disease (as measured by overt clinical symptoms, patterns of activation using fMRI or EEG, functional or behavioral read-outs, disease progression, etc).
  • Construct Validity: The similarity between the physiological or biological basis of the model and the actual human disorder (i.e., genetic, proteomic, metabolomic markers).
  • Predictive Validity: The probability that a clinically validated therapeutic agent (biologic or small molecule) will have the same effects in the animal model or model system as it will in the intended clinical population.  By definition, the evaluation of predictive validity requires a validated molecular tool that has been shown to alter disease progression in humans.  Since these tools do not necessarily exist for many neurological diseases, it is not always possible to obtain true evidence of predictive validity until the candidate therapeutic is actually tested in humans.  Therefore, it may not always be possible to evaluate the predictive validity of a new animal model or model system.  However, it is important to include evaluations of predictive validity (to the extent possible).

Internal Validity

  • Internal validity addresses the consistency of the experimental design.
  • In order to demonstrate internal validation, it is important to evaluate and understand the precision, reliability, sensitivity, accuracy, and dynamic range characteristics of the endpoints used to assess the effect of therapeutic or physiological intervention in the animal model or model system.
  • In addition, it is essential that the general experimental design procedures utilized in characterizing the model are conducted in a rigorous manner, utilizing randomization, blinding and the appropriate power analysis.

Pharmacodynamic Markers

What are pharmacodynamic (PD) markers?

  • PD markers are indicators of biological responses to a therapeutic agent.

Are biomarkers and PD markers the same thing?

  • PD markers are a type of biomarker.  Biomarkers are indicators of normal biological processes, pathogenic processes or biological responses to a therapeutic agent.

What are examples of PD markers?

  • PD markers can reflect both proximal and remote biological responses to a therapeutic agent.
    • Examples of proximal PD markers include receptor occupancy and residence time, phosphorylation of a protein in the direct molecular target signaling pathway, changes in substrate or product levels of the target enzyme, etc.
    • Examples of remote PD markers include phosphorylation of a protein in a signaling pathway downstream from the therapeutic target, fMRI, evoked potentials, EEG, physiological responses to the therapeutic agent, behavioral changes thought to be associated with the therapeutic target, etc.

How are PD markers related to efficacy?

  • Efficacy is defined as an indicator of a desired clinical endpoint.  Therefore, there are cases where a PD marker (particularly a remote PD marker) indicates efficacy.  However, there are also many cases where the molecular target of a disease is unknown and the PD marker is only an indicator that the therapeutic agent engaged with the intended molecular target.  In this latter case, evidence of target engagement can be used to understand why a therapeutic agent was effective or ineffective in clinical testing.

What are some characteristics of a good PD marker?

  • The PD marker provides a biologically meaningful and quantitative index of target engagement.
  • The PD marker can be measured in a reliable and accurate fashion in both preclinical and clinical settings.


  • In vivo efficacy is the capacity for a therapeutic effect of a given intervention, reflecting activity in a desired preclinical or clinical endpoint.  If efficacy is establish, an intervention is likely to be significantly better than the negative control or placebo, with which it will have been compared.
  • In pharmacology, in vitro efficacy (Emax) is the maximum achievable response from a drug.


  • The science of pharmacokinetics attempts to discover the fate of a drug from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics describes how the body affects a specific drug after administration through the mechanisms of absorption and distribution, as well as the chemical changes of the substance in the body (e.g. by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), and the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of drugs may be affected by elements such as the site of administration and the dose of administered drug. These may affect the absorption rate. Pharmacokinetics is often studied in conjunction with pharmacodynamics, the study of a drug's pharmacological effect on the body.

Testing Paradigm

  • Behavioral or environmental model that elicits traits or phenotype observed in a diseased population.

Translational Model

  • Animal model or ex vivo model system that recapitulates the phenotypic or physiological characteristics of a defined disorder, using endpoints that can be measured in a preclinical and clinical species.

Translational Endpoint

  • Clinically relevant and feasible measures that reflects the effect of a therapeutic agent in a preclinical or clinical setting.