Terms and Definitions

A · B · C · D · E · F · I · M · O · P · Q · R · S · T · V

A

accelerated approval

Regulatory mechanism by which new drugs¹ meant to treat serious, life-threatening diseases and that provide meaningful therapeutic benefit to patients over existing treatments can be approved on the basis of adequate and well-controlled clinical trials establishing that the drug has an effect on a reasonably likely surrogate endpoint or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity (intermediate clinical endpoint). Postmarketing confirmatory trials have been required to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit. For more information, see also chapter on Reasonably Likely Surrogate Endpoint.

Relevant Links:

FDA/Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics

analytical validation

A process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include specimen collection, handling and storage procedures). This is validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’s usefulness. For more information, see also chapter on Validation.

assay

An analytic procedure for detecting or measuring the presence, amount, state or functional activity of a biomarker. An assay is one component of a test, tool, or instrument.

Assessment

The interpretation or the evaluation of the measurement.

B

biomarker

A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions. Biomarkers may include molecular, histologic, radiographic, or physiologic characteristics. A biomarker is not a measure of how an individual feels, functions, or survives. Categories of biomarkers include:

• susceptibility/risk biomarker
• diagnostic biomarker
• monitoring biomarker
• prognostic biomarker
• predictive biomarker
• response biomarker
• safety biomarker

For more information, see also chapter on Contents of a Biomarker Description.

Relevant links:

FDA/Center for Drug Evaluation and Research Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools

FDA/Center for Drug Evaluation and Research Biomarker Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Drug Development Tools (DDT) Qualification Programs Webpage

FDA/Center for Devices and Radiological Health Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff: Medical Device Development Tools

FDA/Center for Devices and Radiological Health Medical Device Development Tools (MDDT) Webpage

C

candidate surrogate endpoint

An endpoint still under evaluation for its ability to predict clinical benefit.

clinician-reported outcome

A type of clinical outcome assessment. A measurement based on a report that comes from a trained health-care professional after observation of a patient’s health condition. Most ClinRO measures involve a clinical judgment or interpretation of the observable signs, behaviors, or other manifestations related to a disease or condition. ClinRO measures cannot directly assess symptoms that are known only to the patient. ClinRO measures include:

• Reports of particular clinical findings (e.g., presence of a skin lesion or swollen lymph nodes) or clinical events (stroke, heart attack, death, hospitalization for a particular cause), which can be based on clinical observations together with biomarker data, such as electrocardiogram (ECG) and creatine phosphokinase (CPK) results supporting a myocardial infarction
• Rating scales, such as:
  • Psoriasis Area and Severity Index (PASI) for measurement of severity and extent of a patient’s psoriasis
  • Hamilton Depression Rating Scale (HAM-D) for assessment of depression

clinical benefit

A positive clinically meaningful effect of an intervention, i.e., a positive effect on how an individual feels, functions, or survives.

clinical outcome

An outcome that describes or reflects how an individual feels, functions or survives.

clinical outcome assessment

Assessment of a clinical outcome can be made through report by a clinician, a patient, a non-clinician observer or through a performance-based assessment. There are four types of COAs.

• clinician-reported outcome
• observer-reported outcome
• patient-reported outcome
• performance outcome

Relevant links:

FDA/Center for Drug Evaluation and Research Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools

FDA/Center for Drug Evaluation and Research Clinical Outcome Assessment Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Drug Development Tools (DDT) Qualification Programs Webpage

FDA/Center for Devices and Radiological Health Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff: Medical Device Development Tools

FDA/Center for Devices and Radiological Health Medical Device Development Tools (MDDT) Webpage

clinical utility

The conclusion that a given use of a medical product will lead to a net improvement in health outcome or provide useful information about diagnosis, treatment, management, or prevention of a disease. Clinical utility includes the range of possible benefits or risks to individuals and populations.

clinical validation

A process to establish that the test, tool, or instrument acceptably identifies, measures, or predicts the concept of interest. For more information, see also chapter on Validation.

ClinRO

See clinician-reported outcome.

COA

See clinical outcome assessment.

COU

See context of use.

companion diagnostic

A medical device, usually an in vitro diagnostic (IVD) device, that provides information that is essential for the safe and effective use of a corresponding therapeutic product. The use of a companion diagnostic with a therapeutic product is typically stipulated in the instructions for use in the labeling of both the diagnostic device and the corresponding therapeutic product, including the labeling of any generic equivalents of the therapeutic product.

Relevant links:

FDA/FDA/Center for Devices and Radiological Health Companion Diagnostics Webpage

FDA/FDA/Center for Devices and Radiological Health List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) Webpage

concept

In a regulatory context, the concept is the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to capture (or reflect).

context of use

A statement that fully and clearly describes the way the medical product development tool is to be used and the regulated product development and review-related purpose of the use.

D

diagnostic biomarker

A biomarker used to detect or confirm presence of a disease or condition of interest or to identify individuals with a subtype of the disease. For more information, see also chapter on Diagnostic Biomarker.

digital health technology

A system that uses computing platforms, connectivity, software, and sensors for healthcare and related uses. These technologies span a wide range of uses, from applications in general wellness to applications as a medical device. They include technologies intended for use as a medical product, in a medical product, or as an adjunct to other medical products (devices, drugs, and biologics). They may also be used to develop or study medical products.

E

endpoint

A precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question. A precise definition of an endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used, and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined.

expedited access

A voluntary program for certain medical devices that demonstrate the potential to address unmet medical needs for life threatening or irreversibly debilitating diseases or conditions. Under the Expedited Access Pathway (EAP) Program, the FDA works with device sponsors to try to reduce the time and cost from development to marketing decision without changing the FDA's standards.

Relevant Links:

FDA/ Center for Devices and Radiological Health Guidance for Industry and Food and Drug Administration Staff: Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions

FDA/ Center for Devices and Radiological Health Expedited Access Pathway Program Webpage

F

fit-for-purpose

A conclusion that the level of validation associated with a biomarker or COA is sufficient to support its proposed use.

I

intended use

The specific clinical circumstance or purpose for which a medical product or test is being developed. In the regulatory context, “intended use” refers to the objective intent of the persons legally responsible for the labeling of medical products.²

intermediate clinical endpoint

In a regulatory context, an endpoint measuring a clinical outcome that can be measured earlier than an effect on irreversible morbidity or mortality (IMM) and that is considered reasonably likely to predict the medical product’s effect on IMM or other clinical benefit. The intermediate clinical endpoint may be a basis for full approval if the effect on the endpoint is considered clinically meaningful. It may also be a basis for accelerated approval if the IMM effect is considered critical for use of the drug or for expedited access for medical devices intended for unmet medical need for life threatening or irreversibly debilitating diseases or conditions.

• Example: Exercise tolerance has been used as an intermediate clinical endpoint in trials of device treatments for heart failure.
• Example: A treatment for preterm labor was approved based on a demonstration of delay in delivery. Under accelerated approval, the sponsor was required to conduct postmarketing studies to demonstrate improved long-term postnatal outcomes.

Relevant Links:

FDA/Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics

FDA/Center for Devices and Radiological Health Guidance for Industry and Food and Drug Administration Staff: Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions

FDA/ Center for Devices and Radiological Health Expedited Access Pathway Program Webpage

M

measurement

The obtained value using a test, tool, or instrument.

medical product development tool

Methods, materials, or measurements used to assess the effectiveness, safety, or performance of a medical product. In a regulatory context, examples of MPDTs are clinical outcome assessments, assessments of biomarkers, and non-clinical assessment methods or models.

Relevant links:

FDA/Center for Drug Evaluation and Research Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools

FDA/ Center for Drug Evaluation and Research Animal Model Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Biomarker Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Clinical Outcome Assessment Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Drug Development Tools (DDT) Qualification Programs Webpage

FDA/Center for Devices and Radiological Health Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff: Medical Device Development Tools

FDA/Center for Devices and Radiological Health Medical Device Development Tools (MDDT) Webpage

MPDT

See medical product development tool.

monitoring biomarker

A biomarker measured repeatedly for assessing status of a disease or medical condition or for evidence of exposure to (or effect of) a medical product or an environmental agent. For more information, see also chapter on Monitoring Biomarker.

O

observer-reported outcome

A type of clinical outcome assessment. A measurement based on a report of observable signs, events or behaviors related to a patient’s health condition by someone other than the patient or a health professional. Generally, ObsROs are reported by a parent, caregiver, or someone who observes the patient in daily life and are particularly useful for patients who cannot report for themselves (e.g., infants or individuals who are cognitively impaired). An ObsRO measure does not include medical judgment or interpretation. ObsRO measures include:

• Rating scales, such as:
  • Acute Otitis Media Severity of Symptoms scale (AOM-SOS), a measure used to assess signs and behaviors related to acute otitis media in infants
  • Face, Legs, Activity, Cry, Consolability scale (FLACC), a measure used to assess signs and behaviors related to pain
• Counts of events (e.g., observer-completed log of seizure episodes)

ObsRO

See observer-reported outcome.

outcome

The measureable characteristic (clinical outcome assessment, biomarker) that is influenced or affected by an individuals’ baseline state or an intervention as in a clinical trial or other exposure.

outcome assessment

An assessment of an outcome that results in recorded data point(s) (e.g., for a biomarker or clinical outcome assessment).

P

patient-reported outcome

A type of clinical outcome assessment. A measurement based on a report that comes directly from the patient (i.e., study subject) about the status of a patient’s health condition without amendment or interpretation of the patient’s response by a clinician or anyone else. A PRO can be measured by self-report or by interview provided that the interviewer records only the patient’s response. Symptoms or other unobservable concepts known only to the patient can only be measured by PRO measures. PROs can also assess the patient perspective on functioning or activities that may also be observable by others. PRO measures include:

• Rating scales (e.g., numeric rating scale of pain intensity or Minnesota Living with Heart Failure Questionnaire for assessing heart failure)
• Counts of events (e.g., patient-completed log of emesis episodes or micturition episodes)

PerfO

See performance outcome.

performance outcome

A type of clinical outcome assessment. A measurement based on standardized task(s) actively undertaken by a patient according to a set of instructions. A PerfO assessment may be administered by an appropriately trained individual or completed by the patient independently. PerfO assessments include:

• Measures of gait speed (e.g., timed 25 foot walk test using a stopwatch or using sensors on ankles)
• Measures of memory (e.g., word recall test)

predictive biomarker

A biomarker used to identify individuals who are more likely than similar individuals without the biomarker to experience a favorable or unfavorable effect from exposure to a medical product or an environmental agent. For more information, see also chapters on Predictive Biomarker and Understanding Prognostic versus Predictive Biomarkers.

PRO

See patient-reported outcome.

prognostic biomarker

A biomarker used to identify likelihood of a clinical event, disease recurrence or progression in patients who have the disease or medical condition of interest. For more information, see also chapters on Prognostic Biomarker and Understanding Prognostic versus Predictive Biomarkers.

Q

qualification

A conclusion, based on a formal regulatory process, that within the stated context of use, a medical product development tool can be relied upon to have a specific interpretation and application in medical product development and regulatory review.

Relevant links:

FDA/Center for Drug Evaluation and Research Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools

FDA/ Center for Drug Evaluation and Research Animal Model Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Biomarker Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Clinical Outcome Assessment Qualification Program Webpage

FDA/Center for Drug Evaluation and Research Drug Development Tools (DDT) Qualification Programs Webpage

FDA/Center for Devices and Radiological Health Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff: Medical Device Development Tools

FDA/Center for Devices and Radiological Health Medical Device Development Tools (MDDT) Webpage

R

reasonably likely surrogate endpoint

An endpoint supported by strong mechanistic and/or epidemiologic rationale such that an effect on the surrogate endpoint is expected to be correlated with an endpoint intended to assess clinical benefit in clinical trials, but without sufficient clinical data to show that it is a validated surrogate endpoint. Such endpoints may be used for accelerated approval for drugs and potentially also for approval or clearance of medical devices. In the case of accelerated approval for drugs, postmarketing confirmatory trials have been required to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit.³ For more information, see also chapter on Reasonably Likely Surrogate Endpoint.

Relevant Links:

FDA/Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics

response biomarker

A biomarker used to show that a biological response, potentially beneficial or harmful, has occurred in an individual who has been exposed to a medical product or an environmental agent.

Pharmacodynamic biomarker: A response biomarker that indicates biologic activity of a medical product or environmental agent without necessarily drawing conclusions about efficacy or disease outcome or necessarily linking this activity to an established mechanism of action. Potential uses of a pharmacodynamic biomarker include establishing proof-of-concept, assisting in dose selection or measuring a response to medical products or environmental agents, including the use as a measure of potential harm. In some cases, such measures may be secondary endpoints in clinical trials and may be described in labeling.

Surrogate endpoint biomarker: A response biomarker that is an endpoint used in clinical trials as a substitute for a direct measure of how a patient feels, functions, or survives. A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict that clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.

From a U.S. regulatory standpoint, surrogate endpoints and potential surrogate endpoints can be characterized by the level of clinical validation:

• validated surrogate endpoint
• reasonably likely surrogate endpoint
• candidate surrogate endpoint

For more information, see also chapter Response biomarker.

S

safety biomarker

A biomarker measured before or after an exposure to a medical product or an environmental agent to indicate the likelihood, presence, or extent of toxicity as an adverse effect. For more information, see also chapter on Safety Biomarker.

surrogate endpoint

An endpoint that is used in clinical trials as a substitute for a direct measure of how a patient feels, functions, or survives. A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict that clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.

From a U.S. regulatory standpoint, surrogate endpoints and potential surrogate endpoints can be characterized by the level of clinical validation:

• validated surrogate endpoint
• reasonably likely surrogate endpoint
• candidate surrogate endpoint

For more information, see also chapters on Reasonably Likely Surrogate Endpoint and Validated Surrogate Endpoint.

Relevant Links:

FDA/Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics

FDA/ Center for Devices and Radiological Health Guidance for Industry and Food and Drug Administration Staff: Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions

FDA/ Center for Devices and Radiological Health Expedited Access Pathway Program Webpage

susceptibility/risk biomarker

A biomarker that indicates the potential for developing a disease or medical condition in an individual who does not currently have clinically apparent disease or the medical condition. For more information, see also chapter on Susceptibility/Risk Biomarker.

T

test, tool, or instrument

An assessment system comprising three essential components: 1) materials for measurement; 2) an assay (i.e., for biomarkers) or method or procedure (i.e., for COAs) for obtaining the measurement; and 3) method and/or criteria for interpreting those measurements.

V

validated surrogate endpoint

An endpoint supported by a clear mechanistic rationale and clinical data providing strong evidence that an effect on the surrogate endpoint predicts a specific clinical benefit. A validated surrogate endpoint can be used to support marketing approval of a medical or tobacco product in a defined context without the need for additional studies to demonstrate the clinical benefit directly. Although the term has been used in a conceptually broader way, from a U.S. regulatory standpoint, a validated surrogate endpoint almost always refers to a biomarker. For more information, see also chapters on Validated Surrogate Endpoint and Validation.

validation

A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose. For biomarkers, elements of validation include but are not limited to the following:

• analytical validation
• clinical validation

For more information, see also chapter on Validation.