DoD Prostate Cancer Biomarker Development Award
Many putative prostate cancer biomarkers have been discovered in recent decades. The vast majority of these biomarkers have not been validated or qualified for clinical use, or such studies have been conducted on only a very limited basis, e.g., within a single institution. Thus, the number of markers that have been translated to clinical practice is very small, despite the known limitations of the current standard of care using the biomarker prostate specific antigen (PSA). The PCRP Biomarker Development Award was introduced in FY12 to fund near-term validation or qualification studies that will advance known prostate cancer biomarkers into the clinical setting. Specifically, this award will support high-impact research aimed at multi-institutional validation and/or qualification of prostate cancer biomarkers for crucial decision making in prostate cancer management, including detection of aggressive disease, prognosis and progression, and prediction and assessment of response to therapy. It is anticipated that studies supported through this award will produce clinically useful biomarkers that will provide improved specificity for detection of clinically relevant prostate cancer, as well as distinguish between aggressive and indolent disease, which will in turn reduce the burdens of prostate cancer overtreatment and improve the clinical management of this disease. Proposed projects should demonstrate a high potential for commercialization and clinical use of the projectsÂ’ outcomes. As such, the inclusion of clinical trials is allowed. It is the responsibility of the Principal Investigator (PI) to clearly articulate the potential near-term impact of the study on current clinical practice for prostate cancer management. Due to the expectation for near-term impact, studies aimed at discovery of new biomarkers, studies using tissues or other samples to further investigate biomarker expression patterns prior to large-scale validation or qualification, or studies in model systems to improve or refine biomarkers are not consistent with the intent of this award mechanism and will not be supported. 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 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, which involves determining the range of conditions under which the biomarker will give reproducible and accurate data.2 Alternatively, biomarker qualification is defined as the evidentiary fit-for-purpose process of correlating a biomarker with biological processes and/or clinical endpoints.3 1 Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69:89-95. 2 Lee JW, Devanarayan V, Barrett YC, et al. 2006. Fit-for-purpose method development and validation for successful biomarker measurement. Pharmaceutical Research 23:312-328. 3 Sistare FD, Dieterle F, Troth S, et al. 2010. Towards consensus practices to qualify safety biomarkers for use in early drug development. Nature Biotechnology 28:446-454. The PCRP recognizes that, to move beyond current practice, a combination of biomarkers including those measured in biofluids (e.g., blood, urine), tissue-based biomarkers that provide optimal patient-centered treatment, and new imaging techniques, are needed. The emphasis for the Biomarker Development Award mechanism is on biomarkers that can be assessed through noninvasive methods; however, other types of studies will be considered for funding. Examples of biomarkers may include, but are not limited to: • circulating tumor cells • signatures of genetic or epigenetic changes • specifically expressed genes, proteins, or metabolites, and • molecular, physiological, and/or immunological imaging entities In addition, the significant heterogeneity of prostate tumors should be well considered in any proposed biomarker project. The molecular, cellular, histopathologic, and clinical heterogeneity of prostate tumors presents challenges to the efficacy of many biomarkers. Therefore, PIs are strongly encouraged to address the complexities of intratumoral heterogeneity and how their validation or qualification efforts, and ultimately the biomarkerÂ’s clinical application, may be impacted. All projects proposed for the Biomarker Development Award must address one of the PCRP overarching challenges and the PCRP focus area of Biomarker Development. Key aspects of this award include: 1. Candidate Biomarker(s) and Evaluation: Applications for this award must include clear descriptions of the candidate biomarker(s) for validation or qualification studies. Projects studying multiple biomarkers are highly encouraged. Applications must also include relevant preliminary data from previously completed 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 validated or qualified, 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 • Availability of a robust analytical assay to reliably and reproducibly assess the validity of the biomarkerÂ’s association with prostate cancer or clinical outcomes • Biological association of the biomarker(s) with prostate cancer (e.g., disease stage/grade, distinguish aggressive/indolent) • Strength of association of changes in biomarker levels with pathological/clinical outcomes • Sufficient sensitivity and specificity to guarantee the biomarker(s) does not detect benign physiological processes of the prostate gland and other organs In addition, applications must include, where appropriate, consideration of the Tumor Marker Utility Grading System (TMUGS)4 and, as applicable, be consistent with current U.S. Food and Drug Administration (FDA) guidance for biomarker validation or qualification. Useful information can be found at the following: • FDA Biomarker Qualification Process: ○ FDA DDT Qualification Process ○ FDA Biomarker Qualification Program ○ FDA Guidance for Industry (Draft) In addition, it is highly recommended that PIs demonstrate appropriate consideration of the literature on optimal design of marker studies.5 2. Multi-institutional Approach: Applications to the PCRP Biomarker Development Award are required to be multi-institutional in their approaches to large-scale biomarker validation or qualification. Importantly, inclusion of independent patient cohorts is an expectation for supported studies. In addition, due to the multi-institutional nature of this award mechanism, the award will accommodate up to three PIs, each of whom will receive a separate award. One partner is identified as the Initiating PI and additional PIs are identified as Partnering PIs. The Initiating and Partnering PIs have different application submission requirements; however, each PI should contribute to the preparation of each of the application components. The PIs may have expertise in similar or disparate scientific disciplines. It is the responsibility of the collaborating investigators to describe how their efforts will combine and synergize to maximize the projectÂ’s outcomes. 3. Leveraging of Resources: The PCRP expects that PIs applying for the Biomarker Development Award will leverage existing prostate cancer resources to address high-impact research ideas. For example, many putative prostate cancer biomarkers have never been validated or qualified nor are they readily available for study beyond the laboratories where they were first discovered. Because these biomarkers are not leveraged for study beyond the original source, other groups expend additional time and resources duplicating efforts. Therefore, this award strongly encourages evidence of leveraging biomarker development efforts. Additionally, this award seeks to leverage other resources, supported by the PCRP or other agencies, such as prostate cancer biorepositories (e.g., Prostate Cancer Biorepository Network [PCBN] [http://www.prostatebiorepository.org/], North Carolina – Louisiana Prostate Cancer Project [PCaP] [http://ncla-pcap.org/index.php]), epidemiological resources, databases of clinical data and/or metadata, transcriptome or proteome datasets, or other existing resources. PIs should consider collaborations with personnel affiliated with established prostate cancer resources. 4 Hayes DF, Bast RC, Desch CE, et al. 1996. Tumor marker utility grading system: A framework to evaluate clinical utility of tumor markers. Journal of the National Cancer Institute 88:1456-1466. 5 For example, McShane LM, Altman DG, Sauerbrei W, et al.; Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. 2005. Reporting recommendations for tumor marker prognostic studies (REMARK). Journal of the National Cancer Institute 97:1180-1184. It is the responsibility of the PI(s) to explain how the proposed research leverages existing resources. Applications should also include evidence to support sufficient accessibility and availability of all materials and resources needed to conduct the study so that the project can commence immediately after an award is made. 4. Implementation Plan: The project(s) must be supported by a detailed plan that identifies critical milestones, outlines the knowledge, expertise, and technical innovations that the investigative team will utilize to achieve the milestones, and explains how the outcomes of the project(s) will be translated to patients in the near term. It is strongly encouraged that PIs begin discussions with the FDA early to determine FDA-driven milestones, which should be incorporated into the implementation plan. The application must include information demonstrating accessibility and availability of human subjects, substances, data, and/or materials necessary for the study so that the project(s) can commence immediately after an award is made. A robust statistical plan and statistical expertise should be included, where appropriate, in proposed investigation(s). 5. Research Team: Applications should include a clear description of a consistent and coordinated research effort, with a robust communications plan, by all investigators involved in the project. The overall effort should be led by one or more experienced PIs with records of successfully leading large, focused projects, and who will combine the resources and expertise of all investigators into a synergistic collaboration to achieve the goal of moving prostate cancer biomarkers to clinical practice. The inclusion of scientific advisors, external to the conduct of the research, is encouraged. The PCRP Science Officer assigned to any resulting award must be invited to participate in periodic research team meetings. The plan for such meetings should be noted in the application. Oral Presentation: An oral presentation to the PCRP Integration Panel (IP) is a requirement for application review as described below: • Programmatic Review, Stage 2: An Initiating PI whose application is selected for final consideration in Stage 2 of the Programmatic Review will be required to give an oral presentation that will be held in the National Capital Area in February 2015.
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