Critical Path

Background | Overview | Letter of Intent | Full Application and Review Criteria | Critical Path

 

Background:
Breast cancer research has resulted in the creation of new knowledge; however, some believe that the practical application of this knowledge has not been effectively encouraged by funding agencies. In addition, “translational research” RFPs (Request for Proposals) and funding decisions do not always adequately define and distinguish translational proposals from those more appropriately funded by traditional granting mechanisms. CBCRP believes that identification of a “critical path” from discovery-to-practical application can allow a better selection of grant applications that are responsive to translational research goals.

In 2003 Best et al. (Cancer Epidemiology Biomarkers & Prevention,12:705-712) distinguished two pathways to practical application of research as follows:
, “….. it is important to view "translational research" to encompass not only the pervasive view of transfer of basic science discoveries into clinical applications ("bench to bedside"), but also its transfer into effective interventions at the population level with active community participation in the process ("bench to trench"). Collaboration between research producers and research consumers in this translational approach is critical to reduce the cancer burden at the population level, the ultimate measure of benefit to all people.”

A conceptualization and stepwise model for the “critical path” was published in the context of smoking/tobacco by Greenwald and Cullen (J. Natl. Cancer Inst., 74:543-551, 1985). They distinguished these phases of cancer control research:

Basic Research & Epidemiology

Phase I: Hypothesis development
Phase II: Methods development
Phase III: Controlled intervention trials
Phase IV: Defined population studies
Phase V: Demonstration and implementation

Nationwide prevention and health services programs

CBCRP receives many excellent research proposals, although most are early on the “critical path.” Most research grant applications are incremental plans and do not attempt substantially overcome barriers and advance topics towards translational endpoints. However, the concept of discrete research phases is useful to: (1) identify logical translational steps for a topic, and (2) to make translational efforts understandable across disciplines as described below.

Objectives and Requirements:
To be responsive to CBCRP’s translational research award, the PI should place the proposed project on a “critical path” leading from basic concept to a measurable impact for the prevention, detection, diagnosis and treatment, reduction in community and social burden, or improved patient quality of life for breast cancer.

Note: a complete presentation for the critical path would include: (1) the original concept and “proof of principle” background related to breast cancer, (2) the PI’s accomplishments in the research topic that brings it closer to translation, (3) the specific barriers to translation and the PI’s strategy to overcome them, (4) an endpoint of practical value that the research would enable (e.g., in the clinic or community), and (5) a “vision” for future implementation that extends the expected endpoints and describes the potential impact at the patient, community, or policy levels.

The applicant should distinguish the proposed "translational project" from non-responsive research that aims to: (1) focus on exploratory/discovery endpoints, (2) develop new hypotheses, or (3) accumulate additional or “incremental” knowledge in a given topic.

Translational “Critical Paths” for Different Disciplines:
We have identified three separate “tracks” for translational research, and listed some phases of the research within these disciplines. The following examples are not intended to be all-inclusive, but merely to assist researchers in completing this portion of the application.

⇒Critical Pathway for Translation of Basic Science Discoveries to Clinical Applications: Over the years, industry and research funding agencies have made major investments in translating basic science discoveries into new detection and diagnostic procedures, drugs, and other clinical treatments. Basic science projects that initiate research along this continuum are appropriate for CBCRP’s IDEA funding mechanism or awards from other agencies (e.g., NIH R01). In addition, CBCRP supports research in the developmental stage by offering IDEA-competitive renewals. Applicants from the basic sciences for a CBCRP translational research award are expected to have assembled a robust body of background data in the basic science and developmental phases, and will be poised for transition to the pre-clinical and clinical phases.

Table 1

Position along pathway Definitions and examples
Basic Science (exploratory)
Not appropriate for CBCRP’s translational research award.
Hypothesis testing and exploring novel paradigms. Envisioning a practical application for breast cancer patients or in prevention efforts. Laboratory, basic science studies.
Developmental
(first phase of translational research)
Not appropriate for CBCRP’s translational research award.
Preliminary “proof-of-concept.” Demonstrating a relationship between basic science work and application potential. Includes:
• Target validation to define causal connection or definitive correlation with breast cancer
• Establishing clear relevance to breast cancer and validation of proposed critical path
• Promising work in breast cancer relevant cell models and initial studies in animal models
• Lead compound development and testing
Pre-Clinical
(testing and validation; “first in man” studies). Eligible for CBCRP’s translational research award.
Definitive “proof of concept”. Pre-clinical development directly leading to testing in human subjects Preparation for direct clinical application, final validation of approach. Final stages of testing of diagnostic or therapeutic modality
• Obtaining final animal model and initial human subjects data sets for new drugs and biomarkers to confirm the translational strategy and level of opportunity.
• Final conceptual and testing/validation phases and early phase clinical trials.
• Testing of new imaging modalities in the animal ? human setting for final proof-of-concept in patients
• Establishing clinical protocols and patient study parameters
Could be included in a project, but not as the focus of the funding. For example:
• Toxicity evaluation, pharmacokinetics, formulation and stability testing of therapeutics, scale-up optimization
Clinical Application (application in the human and clinical setting, implementation or “reduction to practice”). Eligible for CBCRP’s translational research award. Testing of a therapeutic, diagnostic or prognostic for efficacy or utility in humans.
Includes:
• Clinical trials
• Demonstrating impact of the therapeutic, detection, prognostic or chemopreventive approaches in breast cancer
• Use of diagnostic tools to define patient population or guide treatment decisions

 

⇒ Critical Pathway for Interventions to Change Behavior or Provide Supportive Services: In many respects research leading to public health interventions follows a similar “critical path” as the basic science-clinical track described above. Table 2 illustrates the key phases that flow from the Cullen and Greenwald model described earlier.

Table 2

Position along pathway Definitions and examples
Hypothesis development.
Not appropriate for CBCRP’s translational research award.
Hypothesis testing and exploring novel paradigms. Develop hypotheses to link new research findings and an intervention to change behavior. Includes:
• Conceptualizing possible interventions.
• Identifying target populations and delivery systems.
Methods development. Not appropriate for CBCRP’s translational research award.
Developing a more detailed model of a proposed intervention and field methodology. Includes:
• Formulating a strategy for practical application.
• Identification of outcome and process measures.
• Identification of data collection and analysis procedures.
• Refining the proposed intervention and evaluation methods.
Controlled intervention trials and defined population
Studies. Eligible for CBCRP’s translational research award.
Larger scale testing of intervention hypotheses in a well-defined population enabling generalization to ultimate target populations. Including:
• Testing intervention outcomes in an efficacy trial (intervention delivered under “ideal conditions”) or an effectiveness trial (intervention delivered under “real world” conditions).
• Conducting process evaluation to test the underlying theoretical framework and/or to identify factors that mediate outcomes.
Demonstration & implementation. Eligible for CBCRP’s translational research award.

Larger scale studies of adaptation, dissemination and diffusion to other populations and communities.

 

⇒ Critical Pathways for Translational Research in Other Disciplines: The critical pathways for translating research discoveries into medical practices, health systems changes, health policies, or environmental modifications are largely uncharted and may be highly variable. Examples of studies relevant to breast cancer research include:

Table 3

Position along pathway Definitions and examples
Early phase research.
Not appropriate for CBCRP’s translational research award.
Identifying public health, social, environmental or community concerns and needs related to breast cancer and developing the initial strategies to enable translational research. Includes developing researcher-community organization collaborations. Examples include:
• Assessing individual community needs and the effectiveness of current breast cancer practices at the community level
• Cost-effectiveness studies of new approaches to preventing, detecting, diagnosing, or treating breast cancer.
• Examining how methods of disseminating knowledge about new research discoveries influence change in health services and identifying facilitating or impeding factors
• The development of models to simulate effects of a proposed public health or policy changes specific to breast cancer
Mid-level research.
Eligible for CBCRP’s translational research award.
Developing practical applications of previous research findings. Examples include:
• Directly engaging “stakeholders” at the community or other levels to test the early application of new health policy and services models
• Policy research leading to implementation
• Testing interventions to increase dissemination and diffusion of evidence-based practices
Advanced studies.
Eligible for CBCRP’s translational research award.
Demonstration projects to test and refine the effectiveness of different methods and models for the final phases of translating research knowledge into health services delivery, policy, and environmental modifications.