Below is a suggested template that submitters may modify to accommodate their submission data, as needed:
This section should be concise. It should include a description of the disease and/or experimental setting in which the biomarker would be used, the definition of the biomarker (e.g., in the case of genomic biomarkers, whether a SNP, CNV, or differential gene expression signature) and a rationale for its use in drug development, including its context of use.
The introduction should summarize the key characteristics of the biomarker, including;
- Strengths and limitations (e.g., comparison with relevant standard methods where available, presence/absence of information on pertinent species/population).
- Whether it is a single or composite biomarker. If it is a composite biomarker, this section should define its component markers and the mathematical algorithm through which these were selected.
- Objective and design of the studies supporting its use, such as prospective versus retrospective study design, study comparators and sample size.
A summary of the proposed context for intended use of the biomarker should be provided in this section. More details, including the full context of biomarker use, can be described in the next section. Suggested areas for consideration include the following:
- An assessment of expected benefits for the application of the biomarker based upon results of relevant studies, including interpretation of how the biomarker performance supports its use in the proposed context.
- Identification of unresolved issues, an explanation of why they should not be considered as barriers to qualification for the proposed context of use, and a description of plans to resolve them if applicable.
1.2 Context of Use
“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 elements typically comprise a clear COU statement:
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 may include steady state level, peak level, or AUC. The intended characteristic should be clear.
2) Species: The species for which the biomarker can be applied in the qualified context must be clear. The COU should describe whether the use is human or nonclinical (and if so what species).
3) Population: For nonclinical qualifications, articulate whether the biomarker is to be qualified for use in normal, healthy animals or a specific animal model. If clinical qualification is intended, articulate the specific intended population for employing the biomarker (and presumably from which the data to support qualification will be derived).
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,
- Patient/clinical trial subject selection or categorization (e.g., for enrichment or stratification)
- Pharmacodynamic assessment
- Efficacy outcome measure (i.e., an efficacy surrogate endpoint)
- Toxicity biomarker (i.e., demonstration of presence of toxicity)
- Safety biomarker (i.e., demonstration of absence of toxicity)
5) The specific drug development or regulatory decision to be addressed. This should include an explicit decision-tree diagram that identifies how the biomarker(s) will be used for each context of use. Specifically, what drug development/ regulatory decision making context will the biomarker be measured for and what decision will be based upon this biomarker.
In some cases, there may be overlap between the general purpose of use in drug development and the specific drug development or regulatory decision to be addressed. Nonetheless, examples of specific decisions to be addressed may include:
- Eligibility criterion for a specific type of clinical trial
- Dose-response assessment for selection of doses to study in phase 3 study
- Assurance of overall non-toxicity
- Distinguishing between patients with early toxicity vs those without toxicity
- A monitoring parameter for adverse event risk
- Marketing approval decision
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, determine 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 in the COU statement 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)
1.3 Methodology and Results
This section should include a summary of existing nonclinical or clinical studies, including integrated analysis of the biomarker qualification study results as available and individual study synopses.
1.4 Knowledge Gaps and Development Plan
This section should describe the limitations of the existing information that create critical gaps in knowledge for fully justifying the biomarker qualification. Issues encountered during the studies should be described and whether they were resolved or remain to be resolved. This section should include a description of studies proposed to obtain the additional information. If feasible, study designs should be described with moderate detail. Full study protocols are usually not necessary for the initial briefing document and meeting, but may be important for subsequent meetings. The QRT may also request study quality-related documentation for subsequent meetings. If the biomarker development program is planned as a multistep process, this should be described, with details of the initial steps and more general descriptions of the later steps if specific studies are dependent upon results of initial steps. It is helpful to provide a potential time line for the development plan, as feasible.
1.5 Measurement Methodology
This section should describe the methodology for measuring the biomarker, with sufficient detail to understand the physical devices used, specialized software needed (e.g., automated digital image analysis software), key operating characteristics of the measurement system, and general availability of the components (as compared to components possessed only by the submitter and not available to organizations outside the submitter group).
1.6 Specific Questions the Submitter has for CDER
List of references and copies of a few references most pertinent to the submission.
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