"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. This document provides guiding principles in formulating a Context of Use (COU) statement for biomarkers being proposed for qualification through FDA’s Center for Drug Evaluation and Research (CDER) Biomarker Qualification Program (BQP).
A COU is comprised of a concise biomarker Use Statement and a comprehensive description of conditions for the biomarker to be used in the qualified setting, termed the Conditions for Qualified Use. (See also Example of a Context of Use in a Qualification Recommendation for Hypothetical Biomarker) It should be noted that biomarkers recommended for qualification prior to 2012 may not represent this current approach for specifying the use statement and conditions for qualified use.
Figure 1: Appropriately Constructed Context of Use
- Use Statement. The Use Statement should be concise and include the name and identity of the biomarker(s) and purpose for use in drug development.
- Conditions for Qualified Use. The Conditions for Qualified Use should be a comprehensive description of conditions for the biomarker to be used in the qualified setting.
Some of the elements that should be captured in formulating a clear and comprehensive COU statement are provided in Table 1 (see below).
Elements of the COU statement, in particular the conditions for qualified use, may be not fully determined when the Letter of Intent (LOI) is submitted. Nonetheless, submitters should make the COU statement as comprehensive and clear as possible at the time of initiating interactions with the BQP. Submitters should begin to consider major parameters that might constitute conditions for qualified use in a final (qualified) COU when formulating their initial COU statement for the LOI. Elements of the COU statement that will need further determination, as knowledge about the biomarker develops, should be identified early in the Qualification Process.
The COU statement generally is refined and clarified during the Consultation and Advice stage of the Biomarker Qualification Process through discussions between submitters and CDER. A well-developed COU statement can greatly streamline these interactions in the Consultation and Advice stage of the Qualification Process. The CDER Biomarker Qualification Review Team's understanding of the intended COU is of utmost importance in guiding discussions between reviewers and submitters on what evidence is needed to support biomarker qualification.
Elements of Context of Use
Identity of the biomarker
- Specific type of radiologic exam with specific imaging modalities (e.g., MRI, PET, Doppler)
- Specific substance/analyte in physiologic fluid
- Specific genomic biomarker
The term “biomarker” may refer to a single biomarker with a single, specific context of use, or to a “composite biomarker” that is made up of several individual biomarkers combined in a stated algorithm to reach a single interpretive readout.
A context of use applies to the composite biomarker as a unified entity. Individual components of the composite biomarker do not have separate COUs unless they are intended for use as stand-alone biomarkers.
Aspect of the biomarker that is measured and the form in which it is used for biological interpretation
- Specific aspect of radiologic findings such as lesion number, volume, diameter, area, perimeter or other characteristics (e.g., tumor volume).
- Serum level of an analyte; possibly also specified in relation to time (e.g., at a specific time, steady-state, AUC, post-treatment minus pre-treatment)
- Used in graded measurement form or after threshold categorization (e.g., change relative to a reference such as baseline, historical control, or normal range, or X-fold change)
Certain biomarkers may require explicit temporal statements such as the window of measurement time if applicable.
Specify the mode(s) of measurement when applicable (e.g., MRI, PET, and Ultrasound).
Specific physiologic fluid/tissue or site of sampling may need to be noted (e.g., plasma, serum, urine, saliva, sweat, CSF).
Species and characteristics of animal or subjects studied
- Animal species or range of species
- For each species, important characteristics (e.g., strain, age, sex, disease model, healthy)
- Human and important characteristics (e.g., age, race/ethnicity, sex, disease, healthy, genotype, disease phenotype)
Provide the relevant details needed to understand the target species, group of species, or patients for which biomarker qualification is sought.
Purpose of use in drug development
- Demonstration of absence of toxicity (Nonclinical or Clinical).
- Demonstration of organ toxicity without performing extensive histopathology (Nonclinical biomarkers)
- Evaluation of exposure-response
- Utilization in clinical study subject enrollment or randomization (e.g., diagnostic, enrichment, stratification)
A general description of this element will usually be a part (explicit or implicit) of the Use Statement component of the COU. In addition, a more precise description may need to be part of the Conditions for Qualified Use section.
For many biomarkers this will be the biological interpretation of the biomarker measurement, and that interpretation is then applied to make the decision described for element #6.
Drug development circumstances for applying the biomarker
· determination of “no observable adverse effect level” (NOAEL) for a specific toxicity when prior toxicology studies did not identify NOAEL with adequate precision;
· selection of the best drug candidate among several drug candidates based upon a specific toxicity;
· demonstration of activity of the drug on the disease pathophysiology (via an animal disease model)
- Clinical :
· selection of doses to take into phase 3 study (i.e., apply biomarker in dose finding studies intended to predict efficacy);
· ensuring patient safety in dose escalation safety studies;
· demonstration of activity of the drug on the disease pathophysiology (i.e., clinical proof-of-concept studies)
Describe the situation in drug development where application of the biomarker improves the drug development process. This might be a description of a type of problem that arises in drug development and for which the biomarker enables making a decision.
Interpretation, and decision/action based on biomarker
- Biomarker levels above N indicate cellular injury in [organ X]. The NOAEL level is below the exposure in which the signal was observed, and should be used in determining starting doses in clinical studies
- Biomarker levels above N indicate a physiologic response has occurred, and the drug compound can be advanced for development
- The absence of biomarker levels above N indicated no significant organ injury has occurred and the drug candidate(s) with this profile can be advanced for further development
- The absence of biomarker levels above N indicate no significant organ injury has occurred and dosing may continue in such patients
- Patients with biomarker levels greater than N are expected to have an endpoint event rate of approximately Y or greater and should be enrolled in the clinical study
- Patients with the biomarker positive for the presence of Z have at least a N-fold greater risk of an adverse response to drugs acting via mechanism of action Y, and should not be enrolled in clinical studies (or, if the biomarker is a response biomarker, such patients should have dosing discontinued).
This element of the COU statement defines the interpretation that is drawn from measurement of the qualified biomarker and the effect of that interpretation on the drug development program.
For composite biomarkers, the algorithm used to combine components leads to a single interpretation; and that single interpretation is applied to decision-making and has an effect on the drug development program.
For some biomarkers, the decision (drug development action) cannot easily be separated from the description of the purpose and circumstances of use or the interpretation of the biomarker, and two or more of these elements would be combined in phrasing the appropriate condition of use (i.e., there may not be separate statements for each of these elements in all cases).
* The table is a guide to the elements of COU statement but should not be the format for submission of the COU. A COU can be formatted in paragraph form, or as a Use Statement plus Conditions for Qualified Use as a list.
Note: Not all elements in Table 1 are relevant for every biomarker. In addition, the COU statement does not need to have all the elements in the same order as the table. The elements listed in Table 1 should be incorporated on an as-needed basis for the respective COU statement. This list of elements is also not intended to be exhaustive. Some biomarkers have other elements such as drug classes/categories (e.g., drugs that activate a specific receptor or that cause toxicity by a given mechanism), that may need to be stated as part of the COU statement to ensure clarity. Submitters should include these as needed.
Important Considerations in Constructing a COU Statement
The initial COU statement is written as the Use Statement plus the Conditions for Qualified Use for which the submitter proposes they have or will obtain the evidence to support. The COU is refined as additional knowledge accumulates. The proposed COU statement can be modified during the Consultation and Advice Stage based on the evidence. The Use Statement will likely include the identity of the biomarker (or analyte), the general information provided by the biomarker and/or the overall utility in drug development. Some examples of the biomarker Use Statement are:
[Biomarker A] is a measure of non-clinical skeletal muscle toxicity for use in • non-clinical safety assessments of drugs.
[Biomarker B] is a surrogate marker for clinical benefit of drugs used to treat [disease Y] for use as a basis for new drug approval.
[Biomarker C] is a prognostic marker of disease progression in patients with [disease Z] for use as an enrichment factor in [disease Z] treatment studies.
Some biomarkers may have multiple applications in a drug development program that relate to a single purpose of use that is not exclusively specific to any one of the applications. In this case, the decision or impact on the drug development program may be best conveyed with examples of the different specific applications. The Conditions of Qualified Use should describe how, in what animals or subjects, and in what kinds of studies, the biomarker will be applied in the future to be within the qualified COU and not how the biomarker was studied to support qualification. For example:
The COU should not say "evidence to support the biomarker qualification came from dog toxicology studies of up to 7 days of exposure." Rather, it could say "[Biomarker X] can be used in dog toxicology studies of up to 7 days exposure" (if 7 days is the limit of qualification that was determined during the Review stage).
Mode of measurement as part of the COU statement: The biomarker used in the qualified setting may be dependent upon the specific modality and method used for its measurement. These specifics will need to be adequately identified in the qualified conditions of use. For example:
A specific plasma protein as a biomarker would have been measured with one or more specific assay methods to provide the data reviewed during Qualification. The information on qualified conditions of use should identify which assays were used and are known to provide accurate and precise measurements at the time of qualification. The information may provide the important performance parameters or any other assay-related information that will assist users of the biomarker in evaluating whether an alternate assay is also adequate for the biomarker measurement.
An imaging biomarker is obtained using one or more imaging modalities (e.g., MRI, CT, ultrasound), and quantitative measurements assessed using specific methods (e.g., specific software packages). The information on qualified conditions of use should identify which modalities and measurement methods are known to be adequate, and where possible, performance characteristics that enable an assessment of any future modality or software package as an alternative.
1 Guidance for Industry: Qualification Process for Drug Development Tools at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf