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Last Updated: 01/11/19

Clinical Trial Definitions and Case Studies

NIH uses the answers to four key questions to determine Clinical Trial designation.

  1. Does the study involve human participants?
  2. Are the participants prospectively assigned to an intervention?
  3. Is the study designed to evaluate the effect of the intervention on the participants?
  4. Is the effect being evaluated a health-related biomedical or behavioral outcome?

The answers to these questions are based on the purpose and design of the clinical study being proposed. To help clarify the uncertainties in this determination for clinical trials that study imaging research, consider the following definitions and case studies provided:

For further guidance, applicants should consult a program officer within the Cancer Imaging Program or the scientific contact person listed on the FOA.

  • NIH-defined clinical trial: A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

    This definition distinguishes between interventional and observational studies. Applicants should also check the “Clinical Trial Requirements for Grants and Contracts” content on NIH’s Office of Extramural Research website for a complete listing of clinical trial-related policies, other helpful resources, FAQs, and additional case studies.

  • NIH non-exempt human subjects research: Most, but not all, clinical trials in the United States are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are reduced and are outweighed by potential benefits. IRBs are committees that are responsible for reviewing research to protect the rights and safety of people who take part in research, both before the research starts and as it proceeds.

    Since NIH does not require IRB approval of a protocol and informed consent documents at the time an application is submitted, applicants should consult their institution’s IRB before writing and applying to help answer whether your imaging research proposal is a clinical trial involving non-exempt human subjects. Most requirements for protecting human subjects are codified in the law, 45 CFR Part 46.

  • FDA regulated studies: The difference between NIH’s Definition of a Clinical Trial and what FDA will consider a clinical trial under the requirements of its Investigational New Drug (IND) or Device Exemption (IDE) Process affects an NIH application proposing an imaging clinical trial. FDA regulates safety/efficacy studies for certain types of therapies and diagnostics that are related to pharmaceuticals, devices, and biologics. NCI clinical trial grant and contract applicants should know which definition takes precedence and if funded, whether clinical trial, and later summary results information, should be submitted to ClinicalTrials.gov.

    In situations where FDA defines research as a clinical trial, but NIH does not, the NIH will accept FDA’s conclusion, even if the research does not fit NIH’s definition of a clinical trial. Therefore, on the Clinical Trial Questionnaire located on the PHS Human Subjects and Clinical Trials Information form, all four questions must be answered “YES” and the necessary clinical trial information must be provided. Below are three examples of IND studies that meet this acceptance rule:

    (1) NCT00572728: Phase II Study of Fluorine-18 3'-Deoxy-3'-Fluorothymidine (F-18-FLT) in Invasive Breast Cancer

    This study involves the recruitment of patients with locally advanced breast cancer to assess the therapeutic response of neoadjuvant treatments early using [F-18] FLT PET imaging. [F-18] FLT is an investigational radiopharmaceutical agent used to detect active cellular proliferation of malignant tumors. The ability for [F-18] FLT PET to assess response to therapy will be determined by comparing the baseline image and early-therapy imaging results with pathologic complete response to neoadjuvant chemotherapy. This study includes an ongoing collection of safety data and image acquisition parameters to optimize the method.

    (2) NCT02398773: F-18 Fluoroestradiol (FES) PET/CT in Predicting Response in Patients with Newly Diagnosed Metastatic Breast Cancer Receiving Endocrine Therapy

    This study involves the recruitment of patients with newly diagnosed metastatic breast cancer to assess the ability of an [F-18] FES PET/CT imaging procedure to predict response to endocrine therapy. This imaging procedure will use [F-18] FES, a radioactive form of the hormone estrogen, to detect the expression of the estrogen receptor across all sites of metastasis. Each patient will receive first line endocrine therapy followed by 24 months of standard of care surveillance to determine if a negative [F-18] FES PET scan correlates with patients who have progressive disease.

    (3) NCT03405142: Panitumumab-IRDye800 Compared to Sentinel Node Biopsy and (Selective) Neck Dissection in Identifying Metastatic Lymph Nodes in Patients with Head and Neck Cancer

    This study involves the recruitment of head and neck cancer patients scheduled for surgery to assess the accuracy of an investigational intraoperative, image-guided procedure using panitumumab-IRDye800 fluorescent imaging. The study is designed to evaluate improvements in the identification of loco-regional metastatic lesions and the visualization of tumor-positive margins during removal. This includes an assessment of impact on patient survival based on an analysis of residual disease.

Mechanistic Clinical Trials: A clinical trial designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (e.g., trials that study the mechanisms or pathways by which the treatment produces its effect). The NIH gave examples of mechanistic studies that likely qualify as clinical trials in the October 25, 2017 Guide notice. Below are imaging-specific examples that experimentally manipulates the biological environment to understand relationships and characterize the pathophysiology of a disease:

(1) NCT01562223: Studying Repeated Magnetic Resonance Imaging (MRI) using Dynamic-Contrast Enhanced (DCE-MRI) and Diffusion-Weighted Imaging (DW-MRI) in Patients Diagnosed with Prostate Cancer

This mechanistic imaging study is designed to assess the use of novel MRI contrast methods for prostate cancer diagnosis. Participants with a recent diagnosis of adenocarcinoma of the prostate will undergo successive DCE-MRI and DWI-MRI examinations. The purpose is to establish the relationship between tumor aggressiveness and novel biomarkers for angiogenesis identified on DCE-MRI and changes in cellular density identified on DWI-MRI. The establishment of these noninvasive imaging tools for characterization of tumor presence, growth, and aggressiveness may help improve the clinicians’ ability to stage and treat the disease.

(2) NCT03412630: Computed Tomography Perfusion Imaging in Predicting Outcomes in Patients with Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Receiving Bevacizumab

This mechanistic study will evaluate changes in tumor blood flow and its relationship to progression free survival in the primary and recurrent ovarian cancer setting. This study seeks to establish perfusion CT as a non-invasive biomarker for early response to bevacizumab combination chemotherapy for ovarian, fallopian tube and peritoneal carcinoma. Perfusion CT is being evaluated for its ability to accurately assess changes in tumor angiogenesis. This will allow the identification of candidates unlikely to incur benefit from bevacizumab early during initial therapy thus predicting long-term efficacy.

(3) NCT02796729: CEST- Glucose Enhanced MRI for Metastatic Brain Tumors

This mechanistic study compares the ability of two advance MR methods to detect metastatic brain tumors. Participants on study will undergo the Chemical Exchange Saturation Transfer MRI procedure first and then receive an injection of Gd-DTPA for gadolinium-enhanced MRI. Project aims at exploring the relationship MRI relaxation caused by CESTAUC maps will be generated over time and maximum instantaneous tumor contrast calculated using before and after contrast injection MR images to determine detectability of small tumor masses.

Note, NCI does not participate in the NIH R01 and R21 Research Project Grants FOAs. Trials of safety, efficacy, and mechanistic exploratory can be supported via NCI’s PAR-18-560 or PAR-18-020 FOAs.

Basic Experimental Studies with Humans (BESH) FOA — Basic science experimental studies involving humans, referred to in NOT-OD-18-212 as “prospective basic science studies involving human participants” include studies that meet the NIH definition of a clinical trial and meet the definition of basic research. Basic research is defined as a “systematic study directed toward greater knowledge or understanding of the fundamental aspects of phenomena and of observable facts without specific applications towards processes or products in mind.” NCI does not participate in the BESH FOAs currently.

Investigator-initiated Interventional Clinical Trials: A study where the intervention(s) being tested is allocated to a group of study subjects to evaluate its effect on a biomedical or health-related outcome and the subjects are followed prospectively. NIH defined interventions include both therapeutic and diagnostic strategies. Below are two imaging-based interventional studies that seek to guide treatment decisions:

(1) NCT01333033: Randomized Phase II Trial of PET Scan-Directed Combined Modality Therapy in Esophageal Cancer

This randomized phase II trial with a cross-over study design investigates the role of FDG PET/CT in assessing response and directing therapy in patients with esophageal cancer receiving different combinations of chemotherapy: a modified FOLFOX-6 therapy or a carboplatin/paclitaxel treatment. PET/CT imaging is repeated during treatment cycles to identify patients that do not respond for crossing over. The results will determine whether changing chemotherapy during pre-operative chemoradiation improves pathologic complete response.

(2) NCT00983697: FDG-PET/CT in Assessing the Tumor and Planning Neck Surgery in Patients with Newly Diagnosed Head & Neck Cancer

The study involves the recruitment of patients with newly diagnosed head and neck squamous cell carcinoma being considered for surgical resection. The participants will undergo a FDG-PET/CT scan prior to surgical resection and the results will be used by surgeons for surgical planning. The study will collect data on how the inclusion of the PET/CT results impact the determination of extent of disease, disease characterization and prognosis, and compares with the surgical plan originally devised from clinical nodal assessment and CT and/or MRI results.