ASC review criteria: In referring proposals to the Steering Committee with a recommendation for final approval, ASSC will give priority to studies which ASSC believes: (1) contribute to Teen-LABS’ aim of examining a broad range of relevant research questions; (2) make important use of the unique Teen-LABS patient cohort; (3) do not interfere with or duplicate the main Teen-LABS objectives or those of other accepted ancillary studies; (4) produce minimal burden on Teen-LABS participants and minimal demand on Teen-LABS resources, such as blood samples and tissues that are also required for accomplishing the goals of the major Teen-LABS protocols; (5) have valid scientific merit; and (6) could not readily be accomplished as separate projects independent of Teen-LABS. It is a goal of Teen-LABS to facilitate as many high-quality ancillary proposals as possible.
Initial evaluation: ASSC will review submitted proposals at least monthly. Teen-LABS will not carry out an in-depth scientific review of those proposals that will be undergoing significant scientific scrutiny via a peer-review process (e.g., NIH study section). The ASSC will focus on the feasibility, overlap with Teen-LABS projects and study / participant burden. The Teen-LABS Central Study Coordinator will also review the feasibility of the proposed study in relationship to Teen-LABS goals and resources. Some proposals may be highly appropriate for affiliation with Teen-LABS while others may not entirely fulfill qualifications to be an ancillary study. Thus, protocols will initially be categorized into one of five groups, which appear below in decreasing order of appropriateness for the ancillary mechanism:
- The ancillary study’s aims are fully consistent with the overall goals of Teen-LABS, while distinct from those being addressed by the major Teen-LABS aims or protocols. The proposed study makes unique and valuable use of Teen-LABS assets including patients, may involve collecting novel samples and may also use data or samples collected for the main Teen-LABS studies. Based on further evaluation (see below), such studies may be referred to the Steering Committee with a recommendation for approval.
- The ancillary study’s aims supplement those addressed by the major Teen-LABS aims or protocols.
They may utilize data from the core database, may involve collection of at least some novel data not collected for the major Teen-LABS protocols, and may utilize specimens collected for major Teen-LABS protocols (e.g., blood samples, tissues) for novel analyses. Based on further evaluation, such studies may be referred to the Steering Committee with a recommendation for approval.
- The ancillary study’s aims are already addressed to some degree within the Teen-LABS main or substudy aims or protocols or are already addressed by another previously approved ancillary study under way. Such studies are unlikely to be recommended for approval unless the overlap with main or substudy protocols is minimal.
- The ancillary study’s aims are generally outside the overarching goals of the Teen-LABS project. Such studies will not be recommended for approval.
- The ancillary study’s aims are completely separate from Teen-LABS and could be met as a free-standing, independent project and do not require an affiliation with Teen-LABS.
- Irrespective of the relevance of the study’s aims, an ancillary study may not be feasible due to unacceptable demands on Teen-LABS patients, staff, or on the pools of available biological samples. Such studies will not be recommended for approval.
Scientific review: Proposals in categories 1 and 2, and possibly some in category 3, will be further evaluated by the ASSC. The ASSC review of ancillary study proposals that will be submitted to NIH and undergo peer review will include: 1) preliminary review of scientific merit, but will focus on the feasibility of the study for Teen-LABS, and 2) an assessment of any overlap or interference of work already being completed in Teen-LABS. This review is for ASSC purposes only and is not meant to provide extensive scientific feedback to applicants. The latter will be obtained as a result of the detailed scientific review occurring through the regular NIH peer-review system. For protocols which have not obtained or will not obtain rigorous peer review (e.g., proposals that will be funded by unrestricted grant support to a research group), the ASSC, supplemented with other experts as necessary, will conduct its own in-depth scientific review of a proposal. The period of time required for an in-depth review will vary based on the complexity of the study but will generally not be less than three months or more than six months.
During ASSC review, all ancillary studies proposals will be circulated to the PIs of the five Teen-LABS sites for comment. The Teen-LABS Data and Safety Monitoring Board (DSMB) may also be asked to judge the demands the proposed study places on participants and the priority in relation to Teen-LABS objectives.
During ASSC review, all ancillary study proposals will be sent to the PI of the Teen-LABS DCC for review of the budget to assure that Teen-LABS DCC staff and analytical costs are appropriate.
The ASSC will make a recommendation as to whether an ancillary study should be given initial approval. This recommendation will not only consider whether the ancillary study interferes with the Teen-LABS protocols, but will also consider whether it competes with other proposed ancillary studies for limited additional participant or staff time and / or biological resources (e.g., blood and tissues). To maximize efficient use of patients and other resources, the ASSC may recommend that several similar and potentially competing ancillary study proposals be combined. The Steering Committee will determine which ancillary study will receive final approval if several meritorious proposals compete for the same limited Teen-LABS resources.
Conditional approval: If the ASSC determines that any given proposal contains elements that if adjusted would allow for approval, it will be given conditional approval and the PI will be notified with an itemized list of those elements that need to be altered and in what manner in order to gain ASSC approval.
Protocol changes: Applicant PIs must inform the ASSC of any substantial changes from the approved three-page application that appear in the final grant submission no later than four weeks before the grant submission. This requirement applies whether the changes are investigator-initiated or are made due to recommendations from a review group such as the ASSC prior to submission to the sponsor. Substantial changes include, but are not limited to, change of sites, PIs, endpoints, hypotheses and biospecimens needed, major changes in sample sizes, and merging of applications. Simultaneous with notification to the ASSC of proposed changes, these modifications must also be conveyed to the DCC electronically, in a format that includes highlighting of modified sections, so that the DCC has adequate time to allocate Teen-LABS resources necessary to accommodate these changes.
In all instances of substantially altered applications, the ASSC will re-evaluate whether the modified project still merits support as a Teen-LABS-approved ancillary study. Following their receipt, Teen-LABS will also compare all final application documents with approved, preliminary three-page applications. Approval for submission will be withdrawn from any applications that contain considerable but previously undisclosed modifications at that time.
Studies proposing to use stored Teen-LABS specimens: ASSC approval and initial Steering Committee approval for an ancillary study to use stored Teen-LABS specimens will be contingent upon the availability of the requested specimen beyond the needs of core Teen-LABS protocols and approved ancillary studies already under way. Studies which seek to use biological specimens will be using stored resources, which may not be replenishable. Thus, such studies will be rigorously reviewed for their scientific and societal value, uniqueness, and the likelihood of successful completion of the study. Final approval to begin such studies is also contingent on documented availability of necessary funding.
Failure to obtain funding: If, within eight months of initial approval by the committee, an investigator is unsuccessful in obtaining the necessary resources, including funding, the initial approval of the project will generally be withdrawn and the ASSC may at that time approve other proposals, including those requesting to use the same specimens or variables as the unfunded study.
Investigators are required to inform the Coordinating Center of funding decisions within five working days of their receipt, and if unsuccessful, whether a revised application is planned. In the latter case, a revised ancillary study proposal to use Teen-LABS tissues / resources, accompanied by the scientific critique of the initial funding application, must be submitted via the Coordinating Center within the next 60 days for reconsideration by the ASC. If the ASSC recommends approval of the revised application, at its discretion, it keeps the required specimens or other resources available for the project in question for a further eight months, allowing time for submission of the revised application. However, the committee reserves the right to reallocate these Teen-LABS resources should they be required for another project that the ASSC approves. In the absence of such a revised application, the initial approval for the project will be withdrawn.
ASC conflict of interest guidelines: During the evaluation process, if any ASSC member proposes an ancillary study, collaborates with an investigator who proposes an ancillary study, or is affiliated with the institution of an investigator who proposes an ancillary study, he or she will be recused from considering that ancillary study proposal, similar to NIH peer-review policies for avoidance of actual or perceived conflicts of interest.
Duration of initial SC approval: The ancillary PI should specify the planned date of final submission of their grant application to the ASSC in their proposal. Initial Teen-LABS approval should be considered valid for the project for only that one application funding cycle. This stipulation will also be specified in the Teen-LABS approval letter. Investigators who wish to resubmit a revised application after peer review must renew their Teen-LABS approval by submitting a new three-page proposal to Teen-LABS in accordance with the schedule indicated in Table 1. The ancillary PI should attach the critique obtained after peer review as an appendix to the new three-page proposal to aid the ASSC in evaluation of the new proposal.
In addition to a favorable review, the ASSC will consider several additional issues before granting final approval to conduct an ancillary study.
IRB approval: The Steering Committee requires that all ancillary studies receive necessary approvals from IRBs at the individual institutions involved. Documentation of IRB approval must be submitted to the Teen-LABS DCC before an ancillary study can be initiated in conjunction with Teen-LABS.
Confidentiality: Confidentiality of individually identifiable data about Teen-LABS participants must be assured. Teen-LABS provides no assurances that ancillary study investigators will be able to identify and contact participants in the future, particularly after completion of the Teen-LABS project.
Availability of funding: For ancillary study applications that require a further application to NIH or other organizations for funding, initial approval by the Steering Committee constitutes approval to apply for such funding. Final approval by the Steering Committee requires submission, by the PI of the ancillary study application, of documents establishing that a definite commitment for funding has been received. However, because several applications that compete for Teen-LABS resources may receive funding, receipt of such funding does not guarantee final SC approval. In these circumstances the SC would work with the relevant PIs to find compromises that would allow the funded research projects to proceed in a manner that would not place an unacceptable burden on Teen-LABS patients or other resources prior to awarding final SC approval. No data collection or use of Teen-LABS patients, data or other resources may begin without such final approval from the Steering Committee.
Ancillary studies must provide funding for hidden costs: In assessing the acceptability of an ancillary study proposal, the Steering Committee will be concerned with both the explicit and the hidden costs to Teen-LABS entailed by the proposal (e.g., staff time / burden, or other unanticipated costs to the Clinical Centers or Coordinating Center for additional data collection and statistical support, burden or other costs to clinical centers for sample collection and shipping, and burden or other costs to Teen-LABS participating patients). The ancillary study’s PI should provide evidence that adequate support for carrying out all functions required for the ancillary study will be available and that the ancillary study will not add any additional uncovered cost to Teen-LABS.
Agreement to provide severe adverse events reports: Ancillary study applicants must agree to submit to Teen-LABS severe adverse events (SAE) reports as may be required by the Teen-LABS Steering Committee and / or Data and Safety Monitoring Board. These reports are in addition to any SAE reports required by the IRB’s of institutions participating in the ancillary study.