Department of Defense Duchenne Muscular Dystrophy Investigator-Initiated Research Award

• Target discovery
• Drug screening
• Mechanism of action studies

Biomarker Studies
For projects addressing “discovery and qualification of pharmacodynamic, prognostic, and predictive biomarkers,” a biological marker, or biomarker, is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or biological responses to a therapeutic intervention.1 For the purpose of this award, biomarker qualification is defined as the evidentiary fit-for-purpose process of correlating a biomarker with the effects of an agent on biological processes and clinical endpoints.2 Alternatively, biomarker validation refers to the process of ensuring that a biomarker or technology (e.g., imaging) will be accurately and reliably measured through the performance characteristics of a biomarker assay.3 The DMDRP encourages the study of biomarkers that can be detected through minimally invasive procedures (e.g., blood, urine, tissue, imaging). Examples of biomarkers may include signatures of genetic or epigenetic changes, specifically expressed genes, proteins, or metabolites, and molecular, physiological, and/or imaging entities, among others.

Candidate Biomarker(s) and Evaluation: Applications proposing biomarker qualification and/or validation studies should include a clear description of the candidate biomarker(s) to be studied. Applications must include relevant preliminary data from pilot testing that demonstrate the suitability of the biomarker(s) for further testing toward clinical application. Sufficient detail must be provided to demonstrate how the biomarker(s) will be qualified or validated, including the approaches that will be applied to establish feasibility, reliability, and reproducibility, and the criteria that will provide the evidence for evaluating the biomarkers. These criteria may include, but are not limited to:

• Improved performance relative to current, clinically accepted biomarkers
• Biological association of the biomarker(s) with Duchenne (e.g., muscle damage/fibrosis, cardiomyopathy, etc.)
• Strength of association of changes in biomarker levels with pathological/clinical outcomes
• Availability of a robust analytical assay to reliably and reproducibly assess the validity of the biomarker’s association with Duchenne or clinical outcomes
• Evidence that a biomarker is a reliable indicator of target engagement, to support the decision-making process in clinical trials

In addition, applications must be consistent with current U.S. Food and Drug Administration (FDA) guidance for biomarker qualification. Useful information can be found online at the following:
FDA Biomarker Qualification Process:
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284076.htm
• http://www.c-path.org/pdf/FDADraftDDTools.pdf

FDA Office of In Vitro Diagnostics and Radiological Health:
• http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHOffices/ucm115904.htm

All applications must include preliminary data that are relevant to Duchenne and the proposed project. Clinical trials are supported by this award mechanism and, if proposed, require the submission of Attachment 11, Human Subject Recruitment and Safety Procedures.

The FY16 DMDRP strongly supports collaborative research between basic scientists and clinical researchers, and between academic scientists and biotechnology/pharmaceutical industry scientists. Collaborations that bring new perspectives from other disciplines, or bring new investigators into the Duchenne field, are also strongly encouraged.

Optional Nested Resident or Medical Student Traineeship: The IIRA mechanism allows for the inclusion of a Nested Resident or Medical Student Traineeship, which would allow the applicant to request additional funds as described in Section I.E., Funding. The Government reserves the right to fund an application at a lower funding level if it does not meet the eligibility criteria or intent of the optional feature. The intent of the Nested Resident or Medical Student Traineeship is to provide mentored research opportunities in Duchenne. It is expected that the training will provide a valuable opportunity to develop the experience necessary to advance the trainee’s research career in Duchenne. Only one traineeship may be requested per application. Plans for training and mentorship must be well developed and clearly described by the PI in the Statement of Traineeship.