Seminars articleDevelopment of a translational medicine protocol for an NCTN genitourinary clinical trial: Critical steps, common pitfalls and a basic guide to translational clinical research
Introduction
Translational medicine (TM) components of prospective clinical trials provide an invaluable opportunity to test hypotheses that contribute to our knowledge of human disease biology and/or the mechanism of action of a given therapeutic intervention. Our ability to sample tumors and their microenvironment, and the depth and breadth of biological information that can be extracted from them, has increased exponentially in recent years. This information is critical to guide the next steps clinical research if we are to accelerate the pace of progress in cancer treatment [1]. Thus, TM studies should be considered key components of any clinical trial. However, TM studies are costly and biologic sampling can impose significant morbidity on our patients. Therefore, TM investigators should be engaged early in the design process (similar to a statistician) to ensure that the most imperative research questions are rigourosly defined, that the obtained specimens can be used to answer them and that the results will serve as the foundation for additional studies. In this review, we focus on TM studies in the context of the National Cancer Institute's National Clinical Trials Network (NCTN) trials and offer a description of the genesis of TM components, methods in sample acquisition and biomarker research, and a guide to funding mechanisms, in order to provide a blueprint for future TM research protocols. While TM studies can take many forms, the research discussed primarily focusses on basic and translational research involving molecular, cellular and immunobiology.
Section snippets
The role of TM research in an NCTN trial
The TM component of an NCTN trial should develop in parallel with the conception of the clinical protocol (Fig.1). Identifying the specific questions that can be asked in an NCTN trial and how that clinical outcome will be supported by biology, including biomarkers for response, are the foundation of TM research. At a practical level, the number of patients and corresponding biospecimens will affect the questions to be addressed.
Developing research questions
For NCTN trials, the TM research is centered around the major hypothesis of the clinical trial with both the clinical and TM questions directed towards hypothesis-driven research. Some general examples of TM questions include “if the clinical trial is successful, the mechanism of success is likely due to what cause and can we prove that at the cellular or molecular level” or “we think the patients in the trial who will respond the best to the treatment will express this biomarker.” These
The translational team
The collaboration of clinician/trialists, scientists, and biostatisticians involved in the development of a TM protocol is essential to construct a well-developed and relevant research protocol. This team is assembled at the time of protocol development and includes stakeholders with experience in the field of study. At least one member of the TM team should have experience in developing TM concepts, budgets, and applying for funding. The role of each team member is critical and often
Biomarker research
The identification of biomarkers that are either predictive or prognostic is an important aspect of NCTN trials (Fig.2) [2]. For inclusion in a clinical trial, a biomarker should have strong supporting prior data to justify its inclusion in a TM project. These biomarkers should have been evaluated in multiple retrospective settings, and the TM project is an opportunity for prospective validation. Depending on the structure of the clinical trial, biomarkers should be classified as either
Budgets – funding the TM project
Funding of TM research is one of the most important challenges in clinical research and the responsibility of the TM team. While the clinical trial is often funded by a combination of standard-of-care (insurance) and NCI/CTEP, the TM component usually receives little to no funding through the NCI. Once approved by CTEP, most trials have a minimum budget that includes funding for obtaining slides for banking and resources for one tube of blood. The pharmaceutical industry is sometimes able to
Cores of specialization
The NCI has recently supported the development of Cancer Immune Monitoring and Analysis Centers (CIMACs) that will conduct focused immunotherapy support for NCTN trials [9]. The overarching goals of these centers is to identify molecular biomarkers that define immune response and support specialized centers of excellence for NCTN trials. CIMACs are supported by a U24 mechanism with the goal of (1) predicting the likelihood of benefit or toxicity from immune therapies, (2) helping to develop
Managing trial patient bioresources
The identification of what biologic resources are necessary to answer TM questions is a fundamental question in TM protocols. Specimens are often collected at the time of registration, but they can also be collected during the course of a trial. Coordination of shipping, including batching of samples may require orchestration with the biobank and individual sites. The TM coordinator will need to develop collection kits and/or specific shipping directions that can be implemented across sites. In
Conclusion
The TM component of an NCTN trial complements the clinical trial and can provide important information that directly affects patient care and future trials. Barriers to TM research are the amount of resources and funding that are necessary to complete TM research projects. A carefully developed TM strategy can change clinical care and provide and unprecedented avenue of future of discovery.
References (9)
Translational research in the National Cancer Institute's cooperative groups
Clin Adv Hematol Oncol
(2014)Biomarker: Predictive or Prognostic
J Clin Oncol Off J Am Soc Clin Oncol
(2015)- et al.
PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data
Immunotherapy
(2017) - et al.
Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents
Clin Cancer Res Offic J Am Assoc Cancer Res
(2010)
Cited by (0)
Funding: JM is supported by a SEED grant from the HOPE Foundation, BX003692-01 from the VHA and the John P. Hanson Foundation.