“Context of use”, or COU, is a comprehensive and clear statement that describes the manner of use, interpretation, and purpose of use of a biomarker in drug development. The following is a description of typical elements  that comprise a clear COU statement and are meant to provide a general understanding of the biomarker qualification context of use statement. The context of use statement does not need to have isolated bulleted items corresponding the following listing; it is often better written as a short paragraph encompassing these aspects:

 

1) Identification of the biomarker: The specific biomarker (and biomarker characteristic if not self-evident) should be articulated. For example, if using an imaging parameter for a pathologic lesion the biomarker may be the “number” of lesions, the “size” of lesions, or some other “characteristic”. Serum response biomarker characteristics include steady state level, peak level, or AUC. The intended characteristic should be clear.

 

2) Species: The species intended - human or nonclinical; if nonclinical, what animal species?

 

3) Population: For nonclinical qualifications is the use in normal healthy animals or what animal models are to be studied? If clinical qualification is intended, what is the specific intended population for employing the biomarker (and to whom  the data to support qualification must relate )?

 

4) General purpose of use in drug development, which often needs to also identify the intended interpretation of the biomarker to ensure clarity: Examples include, but are not limited to,

a.  Patient /clinical trial subject selection or categorization (e.g., for enrichment or stratified randomization )

b.  Pharmacodynamic assessment

c.  Efficacy outcome measure (i.e., an efficacy surrogate endpoint)

d.  Assessment of mechanism of action (e.g., confirmation of expected mechanism of action)

e.  Toxicity biomarker (i.e., demonstration of presence of toxicity)

f.  Safety biomarker (i.e., demonstration of absence of toxicity)

 

5) The specific drug development or regulatory decision to be addressed. Examples include:

a.  eligibility criterion for a specific type of clinical trial

b.  dose-response assessment for selection of doses to study in phase 3 study

c.  assurance of overall non-toxicity

d.  distinguishing between patients with early toxicity vs. those without toxicity

e.  marketing approval decision

f.  determining the indicated population in labeling

 

6)   If not contained in the phrasing used for the general or specific use description, a statement of what the measurement is intended to mean (e.g., confirm the patient has disease X, confirm the patient is in an active phase of disease Y when Y has a naturally waxing and waning course, the patient is biologically capable of responding to drug Z, or has responded to the drug).   In many cases items 4, 5, 6 will not be stated as distinctly separate thoughts, and doing so is not necessary. A single thought (sentence) might incorporate all three aspects in a clear and concise manner.  

 

7) Other specific limits on use or decision implications (e.g., limitations of drug or drug class applicability).