Adequate and well-controlled (A&WC) studies — These are studies used to support drug marketing authorization and intended to provide substantial evidence of effectiveness required by law to support a conclusion that a drug is effective (see 21 CFR 314.126). Other studies are termed exploratory studies. This distinction depends on multiple features of a clinical study design and is not necessarily determined by any single aspect of study design. Such features include the nature of the primary endpoint or the rigor of control of the Type I error rate. An A&WC study can have exploratory elements without becoming an exploratory study. The prospectively planned analyses that will support an effectiveness claim should be carefully planned and designed with rigor. A wide variety of other analyses (e.g., exploratory endpoints and post hoc analyses) may be examined with less assurance of control of Type I error rate and can suggest directions for subsequent studies.
Adverse events — Symptoms or signs related either to the disease or to the treatment (therapy) for a disease.
Assessment (measure) — An assessment (or measure) is an evaluation of some aspect of a patient that results in a recorded datum.
Biological marker (biomarker) — A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.1
Clinical outcome assessment — A COA is any assessment that may be influenced by human choices, judgment, or motivation and may support either direct or indirect evidence of treatment benefit. Unlike biomarkers that rely completely on an automated process or algorithm, COAs depend on the implementation, interpretation, and reporting from a patient, a clinician, or an observer. The four types of COAs are patient-reported outcome (PRO) measures, clinician-reported outcome (ClinRO) measures, observer-reported outcome (ObsRO) measures, and performance outcome (PerfO) measures.
Clinician-reported outcome (ClinRO) — A ClinRO is based on a report that comes from a trained health-care professional after observation of a patient’s health condition. A ClinRO measure involves a clinical judgment or interpretation of the observable signs, behaviors, or other physical manifestations thought to be related to a disease or condition. ClinRO measures cannot directly assess symptoms that are known only to the patient (e.g., pain intensity).
Concept of interest — The thing measured by an assessment (e.g., pain intensity).
Context of Use — A comprehensive statement that fully and clearly describes the way the COA is to be used and the drug development-related purpose of the use. The context of use defines the boundaries within which the available data adequately justify use of the COA and describes important criteria regarding the circumstances under which the COA is qualified.
COA Qualification — COA qualification represents a conclusion that within the stated context of use, the results of the COA measurement can be relied upon to have a specific interpretation and application as long as there are no serious study flaws and there are no new and conflicting scientific facts not known at the time the qualification was determined. COAs traditionally used may still be acceptable even though they have not been qualified, however, the use of such COAs will continue to be reviewed on a case-by-case basis. For qualified COAs, drug developers will be able to use the COA in the qualified context in IND and NDA/BLA submissions without requesting that the relevant CDER review group reconsider and reconfirm the suitability of the COA.
Drug development tool (DDT) — A DDT is a method (and associated materials) that aids drug development. DDTs include, but are not limited to, biomarkers, clinical trial outcome assessments, and animal models. DDTs suitable for the CDER DDT Qualification process are a subset of all types of DDTs, and should be intended for potential use, over time, in multiple drug development programs. Some DDTs used as clinical trial outcome assessments may sometimes be called an instrument. The term “instrument”, or “tool”, refers to the means to capture data plus all the information and documentation that support its use within the intended context of use.
Effectiveness — An essential component of the basis for marketing approval of a drug; drugs must be safe and effective to justify approval. Effectiveness is defined as a benefit to patients in how they feel, function, or survive due to treatment with the drug.
Endpoint — The way an assessment will be used as a study result and statistically compared among treatment groups to assess the effect of treatment. Endpoints are often named by the assessment measured, but a complete statement of the endpoint should include a full description of what data are collected, and how they are analyzed to support a specific study objective.
Exploratory studies — Studies that are not A&WC, often because they do not rigorously control the Type I error rate or because they use an endpoint that is not suitable to be a basis of marketing approval. Exploratory studies are generally conducted earlier in the drug development program than the A&WC studies and have an important informative role in drug development concerning future choices for A&WC study population and endpoints.
Feels — A patient’s physical sensation (e.g., symptoms) or perceived mental state. A patient may feel pain, feel feverish, or perceive a severely low mood (as with depression).
Functions (functioning) — The manner in which a patient can perform successfully tasks and roles required for everyday living. A patient’s ability to perform specified activities that are a meaningful (to the patient), part of typical (e.g., daily) life.
Health-related quality of life (HRQL) — HRQL is a multi-domain concept that represents the patient’s general perception of the effect of illness and treatment on physical, psychological, and social aspects of life. Claiming a statistical and meaningful improvement in HRQL implies: (1) that all HRQL domains that are important to interpreting change in how the clinical trial’s population feels or functions as a result of the targeted disease and its treatment were measured; (2) that a general improvement was demonstrated; and (3) that no decrement was demonstrated in any domain.
Observer-reported outcome (ObsRO) — An ObsRO is a measurement based on an observation by someone other than the patient or a health professional. This may be a parent, spouse, or other non-clinical caregiver who is in a position to regularly observe and report on a specific aspect of the patient’s health. An ObsRO measure does not include medical judgment or interpretation. Generally, ObsROs are reported by a parent, caregiver, or someone who observes the patient in daily life. For patients who cannot respond for themselves (e.g., infants or cognitively impaired), we encourage observer reports that include only those events or behaviors that can be observed. As an example, observers cannot validly report an infant’s pain intensity (a symptom) but can report infant behavior thought to be caused by pain (e.g., crying). For example, in the assessment of a child’s functioning in the classroom, the teacher is the most appropriate observer. Examples of ObsROs include a parent report of a child’s vomiting episodes or a report of wincing thought to be the result of pain in patients who are unable to report for themselves.
Outcomes — The benefits or harms to a patient who receives an intervention.
Patient-reported outcome (PRO)— A PRO is a measurement based on a report that comes from the patient (i.e., study subject) about the status of a patient’s health condition without amendment or interpretation of the patient’s report 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 (e.g., pain severity or nausea) 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.
Performance outcome (PerfO) — A PerfO is a measurement based on a task(s) performed by a patient according to instructions that is administered by a health care professional. Performance outcomes require patient cooperation and motivation. These include measures of gait speed (e.g., timed 25 foot walk test), memory recall, or other cognitive testing (e.g., digit symbol substitution test).
Proxy-reported outcome — A proxy is a person who reports an outcome as if she/he was the patient him/herself. Proxy reports are not recommended for unobservable symptoms that can be known only by the patient. A proxy-reported outcome is not a PRO but is a measurement based on a report by someone other than the patient reporting as if he or she is the patient. A proxy-reported outcome is not a valid endpoint.
Qualification — A regulatory conclusion that within the stated context of use, the results of assessment with a drug development tool (DDT) can be relied upon to have a specific interpretation and application in drug development and regulatory decision-making.
Quality of life — A general concept that implies an evaluation of the effect of all aspects of life on general well-being. Because this term implies the evaluation of non-health-related aspects of life, it is too general and undefined to be considered appropriate for a medical product claim.
Sign — Any evidence of a disease, health condition, or treatment-related effect that can be observed. Signs can be assessed using PRO, clinician-reported (ClinRO), observer-reported (ObsRO), or performance outcome (PerfO) assessments, as appropriate.
Symptom — Any subjective evidence of a disease, health condition, or treatment-related effect that can be noticed and known only by the patient.
Treatment benefit — The impact of treatment as measured by survival or a COA of how patients feel or function. Direct evidence of treatment benefit is derived from clinical trial effectiveness endpoints that measure survival or a meaningful aspect of how a patient feels or functions in daily life. All other effectiveness endpoint measures provide indirect evidence of treatment benefit (e.g., performance assessments). Treatment benefit can be demonstrated by an advantage in either effectiveness or safety, or both.
1. Biomarkers Definitions Working Group (2001). Clinical Pharmacology and Therapeutics, 69, p. 89 – 95.