CCSC Proposal Evaluation Guidelines

High-quality, clinically annotated biospecimens are a limited resource, and there is particularly high demand for specimens from randomized Phase 3 studies with a positive primary endpoint outcome. The CCSC considers the following factors when determining which proposals should be approved for the use of high-value clinical trial specimens:

1. Priority is given to studies validating fully specified (locked) prediction models and/or validation of pre-specified biomarkers for which substantial supporting evidence is provided.
2. The context of the clinical trial for which specimens are requested should be essential to the questions posed by the proposed study.
3. Data from large, randomized clinical trials should primarily be used to answer definitive correlative science hypotheses.
4. Predictive biomarkers are preferred over prognostic biomarkers.

Although the NCTN-CCSC gives highest priority to validation studies, exploratory or discovery studies may be approved in certain circumstances. The following study characteristics are supportive (though not definitive) of the use of clinical specimens for exploratory studies:

1. The clinical trial involved a rare cancer, as defined by ≤3-6/100,000 new cases per year, and had a negative result.
2. Fewer than 50% of the clinical trial’s biospecimens remain available.
3. The clinical trial was a phase 3 randomized trial that had a negative primary endpoint outcome and either the primary outcome was published more than 5 years prior to proposal review or the experimental agent is no longer under active investigation.
4. The proposed study (such as a slide imaging study) will not consume the specimens, and the specimens will be returned unaltered to the biorepository. If slides have not already been digitized, the proposal will be reviewed by the NCTN-CCSC. If digitization has been completed, the Proposal Submission Form should instead be submitted to PIO for review by the NCI Protocol Review Committee, not the NCTN-CCSC.

Statistical plans for exploratory study proposals must include:

1. Power calculations or precision calculations demonstrating that the proposed sample size is adequate.
2. False discovery control or other precautions to avoid generation of spurious results.
3. Internal and external model validation to identify and avoid over-fitting of complex models, if applicable.

Examples of exploratory proposals that might be considered under these extended criteria:

1. Purely exploratory analyses aiming to discover novel biological subgroups, irrespective of clinical outcomes;
2. High-throughput screening of very large numbers of molecular characteristics, individually or in combination, for their association with clinical outcomes or other clinical or pathological phenotypes (e.g., identification of lists of genes having expression level that correlates with survival or disease phenotype or building a predictor of clinical outcome or adverse event with no strong a priori biological or mechanistic hypotheses).

The CCSC reviews proposals only for the use of banked, non-reserved specimens from completed Phase 2 or Phase 3 NCTN clinical trials. The CCSC does not review proposals for the use of other specimen types, including:

1. Clinical trial samples designated for NCI-reviewed integral or integrated biomarkers.
2. Specimens from phase 1 or small phase 2 trials.
3. Specimens from clinical trials that are still under DSMB oversight or that have not yet reported out their primary endpoints.
4. Specimens from select trials that have their own steering committee for reviewing specimen requests (such as international trials led by non-US groups).
5. Specimens from group biobanking protocols involving specimen collection not associated with a clinical trial, or the trial is not collecting patient outcome data. Proposals to use these specimens are reviewed by the NCI Protocol Review Committee.
6. Specimens from internal NCI collaborative processes, such as the Clinical Trial Sequencing Project or NCI Blue Ribbon Panel.
7. Specimens from non-NCTN pediatric trials or COG trials that are not phase 2/3 or phase 3. Such requests should be directed to the Children’s Oncology Group and the NCI PIO.

What specimens might be in demand from many investigators?

Typically, specimens may be more “in demand” if they were collected in a randomized phase 3 trial that had a positive outcome in their primary endpoint.

What are hallmarks of a good proposal seeking use of NCTN specimens?

Find tips for preparing a competitive proposal on the Proposal Submission and Review page.

Can I isolate RNA or DNA from specimens myself, or must it be done by the biorepository?

The NCTN Group bank must do all nucleic acid isolations. This is done to maintain quality control and to maximize availability and use of the specimens. If you wish isolations to follow a specific protocol, this can be negotiated with the bank.

Can I request a tissue microarray?

Requests for use of biospecimens may include generation of TMAs. Requests should proceed per the process described above and, in the LOI form, include a statement that a TMA is requested. The review will proceed per the standard procedures.

What other specimen resources are available for exploratory studies?

Find additional biospecimen resources through the DCTD Cancer Diagnosis Program (CDP) Human Tissue Specimen Resources page.

Do I need to submit a CCSC proposal if I am requesting digitized scans of H&E-stained slides?

• If slides have already been digitized, the resultant scans are considered data. Requests for scanned data should proceed via the NCTN group that ran the trial. The proposal form should be filled out completely; indication of funding status should be included. These requests will be reviewed programmatically by CTEP/NCI and will not go to the Core Correlative Science Committee.
• Navigator request and proposal submission to the Core Correlative Science Committee for review should proceed as above where tissue slides have not already undergone digitization. Such endeavors are time-consuming and often require opening the tissue blocks to prepare new H&E slides.