Webinar: Discuss New Funding Announcement - Stroke Preclinical Assessment Network (SPAN) to Support Translational Studies for Acute Neuroprotection

September 18, 2018

Location:

Webinar
1-2:30 p.m.m EST
Phone number: 1-650-479-3208
Access # 620 311 854
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Join the webinar event on September 18, 2018 from 1:00 p.m. - 2:30 p.m. EST to discuss new funding opportunity announcements: RFA-NS-18-033 and RFA-NS-18-034 on the Stroke Preclinical Assessment Network.

View webinar slides(pdf, 1093 KB) 

(Application due date December 13, 2018)

  • RFA-NS-18-033 - Stroke Preclinical Assessment Network (SPAN) to Support Translational Studies for Acute Neuroprotection (U01 Clinical Trial Not Allowed)

    The purpose of this funding opportunity announcement (FOA) is to solicit applications of promising neuroprotective drugs/interventions for the Stroke Preclinical Assessment Network (SPAN).  SPAN will support late-stage preclinical studies of putative neuroprotectants to be given prior to or at the time of reperfusion, with clinically relevant long-term outcomes and comorbidities. Parallel testing of the most promising interventions will help to determine if an intervention can improve outcome as compared to reperfusion alone and/or extend the therapeutic window for reperfusion, and if so, guide the selection of the best agent(s) to transition to future Phase II clinical trials (to be conducted through StrokeNet).  SPAN will consist of one Coordinating Center (CC) and up to 6 network sites; this infrastructure is expected to test up to 6 compounds/interventions (one for each of the awarded sites) in animal models of transient cerebral ischemia. The SPAN program will not support any human subjects research.
     
  • RFA-NS-18-034 - Stroke Preclinical Assessment Network (SPAN) to Support Translational Studies for Acute Neuroprotection - Coordinating Center (U24 Clinical Trial Not Allowed)
    The purpose of this funding opportunity announcements (FOAs) issued by NINDS is to invite applications for the Coordinating Center and network sites for the NIH Stroke Preclinical Assessment Network (SPAN).  SPAN will facilitate testing of up to 6 promising neuroprotective drugs or interventions to be given prior to or at the time of reperfusion in experimental models of ischemic stroke (e.g., transient middle cerebral artery occlusion). The awarded network sites will become part of the network and will collaborate with the other awarded sites under the oversight and central coordination provided by the SPAN Coordinating Center.  Applicants for the network sites must propose a promising neuroprotective intervention to be tested within SPAN; awarded sites must agree to  test up to 6 interventions in parallel, including their own. If successful, this network will accelerate the identification of the most promising neuroprotective therapies for future pivotal clinical trials and span the gap between preclinical and clinical testing, in a cost-and time-effective fashion.

 

Related Resources

Stroke Preclinical Assessment Network (SPAN) Frequently Asked Questions

A. Interventions

Q.  Is the purpose of the network to test neuroprotectants in the “classical” sense (i.e. drugs that protect neurons against ischemic injury), or is the notion of neuroprotection broader (i.e. anything that improves outcomes, whether it acts on endothelium, BBB, inflammation, neurons, etc.)?
A.  Proposed interventions are not limited to drugs or compounds that affect neurons. We are interested in anything that can improve functional outcome or extend the time window of intervention in the context of ischemia-reperfusion. While this is a broad definition of neuroprotection, the proposed intervention must be clinically relevant in the context of endovascular therapy.

Q.  Can the proposed intervention be a device?
A.  Yes. But please keep in mind that it must be easily implemented by the other research sites. The applicant should also describe how blinding can be implemented.

Q.  What if the proposed intervention is a drug that is already in use for something else?
A.  We encourage the repurposing of drugs/interventions that are efficacious in another disease/condition, as long as there is strong supporting data indicating that this could work in stroke as well. If this is the case, then you would have to partner with the pharmaceutical company that holds the patent. In fact, one of our goals is to encourage such collaborations and this would be viewed as a strength.

Q.  One of the intervention requirements is that there is human safety data?, so that the intervention can move quickly into clinical trials. Are you thinking of a pipeline for NINDS/StrokeNet trials or for NINDS/pharma partnerships and does this impact how proposed interventions will be reviewed?
A.  Having interventions that can be immediately tested in people is a critical requirement since the overall goal is to find things that can be advanced rapidly to clinical trials. Therefore, partnerships with pharmaceutical companies, while not required, are highly relevant and will be evaluated during the review. These may include the testing of repurposed drugs or drugs that were previously abandoned when pharma dropped out of neuroprotection. Partnerships with StrokeNet sites are also encouraged if they have something that could be moved forward as a neuroprotectant.

Q.  The human safety data seems unusual since the purpose of these announcements is to target investigators who may want to join a preclinical network. Could you please clarify?
A.  The reason why we are specifying the need for human safety is because we hope to attract interventions that have the potential to rapidly advance into clinical trial testing. If something is efficacious in animal models but we still don’t know if it can be safely administered in humans, then this will greatly delay the process. Any new intervention (especially a drug or biologic) would require an IND/IDE from the FDA to proceed with clinical testing. We are interested in interventions that could receive regulatory approval from the FDA to test in patients who have had a stroke. If there is uncertainty, applicants are encouraged to communicate with the FDA to receive guidance on whether additional testing would be needed before they could proceed into a trial. We could consider such an intervention if evidence is presented in the application demonstrating that the treatment is ready to move into clinical testing.

Q.  Based on the requirements for proposed SPAN interventions, it seems that only repurposed or discarded drugs will have any hope of being selected. Are you worried you might miss other promising interventions because of the strict human safety requirement?
A.  The overall goal of SPAN is to identify and test those interventions that can be rapidly moved into a clinical trial. If successful, this approach will be used as a model for the future testing of more experimental approaches for the treatment of stroke. For those interventions lacking human safety data or evidence that the treatment would be ready to move rapidly into trials, NINDS has many other mechanisms for translational research. Please refer to our Division of Translational Research website for more information about other opportunities that may be more appropriate for your intervention.

Q.  Can human safety data be obtained from other clinical trials that don’t necessarily involve ischemic stroke? For example, what if we are repurposing a drug from a non-stroke clinical trial?
A.   This would be reasonable as long as the population from the non-stroke trial isn’t dramatically different from the target stroke population. For example, if the human safety data is from a pediatric trial, then this would not be acceptable.

Q.  Are there any other requirements for specific drugs to be tested?
A.  If you will be working with pharma or any other entity that holds a patent for the specific intervention, then the application must include clear permission allowing its use. The parameters of any such collaborations must also be clearly described in the application.

Q.  Do you expect the team to have published on the intervention they propose or is it equally acceptable to propose a target based on the mechanism and scientific rationale if others have shown efficacy in ischemic stroke models?
A.  The reviewers will consider both preliminary data and whether there is sufficient support provided in published literature on the proposed intervention. It’s not a requirement that the intervention was discovered by the applicant. However, we strongly encourage preliminary data repeating the most relevant experiments in your own lab.

Q.  Do I have to propose an intervention to be part of the network or can I just apply to be a testing site?
A.  We will only consider applications that propose an intervention. However, it is possible to collaborate with another PI who is proposing an intervention if you can provide a specific area of expertise that would strengthen the proposal. For example, you could contribute expertise on a co-morbidity model, or neuroimaging, or behavioral outcome, or a higher species, to an application without proposing your own intervention, but you would not be listed as the PI. The collaboration needs to be detailed in the application. Reviewers will evaluate these types of collaborations.

Q.  Can different labs at different institutions apply to this RFA with the same neuroprotective compound?
A.  Yes, applicants are not expected to know which other applications are coming in, so multiple applications for the same intervention are okay. The primary review group will evaluate each proposal for its preliminary data and the PI’s credentials and experience.  A secondary review with the NINDS Advisory Council will then consider which grants will be selected for funding.  It is unlikely that NINDS will award more than one grant for the same drug/intervention.

Q.  Can I propose more than one putative drug or intervention?
A.  Yes, you can submit more than one application. However, they will be competing against each other and it is highly unlikely that a single site would receive more than one award.

B. Network Logistics

Q.  Will every intervention really be tested under all experimental conditions at each research site?
A.  Yes and no. This is where the adaptive design will come into play. All interventions will be tested by all sites in a series of basic experiments, but it will quickly become apparent that some interventions are better than others. The coordinating center will decide when it’s time to drop a specific intervention, and the research sites won’t know which interventions have been discarded since everything will be blinded by the Coordinating Center. The coordinating center will also design a series of milestones that should help decide which promising interventions will be advanced to multiple other experimental conditions (comorbidities, age, second species, etc.).

Q.  Is the MCAO stroke model the only preclinical animal model that will be considered?
A.  Yes. We want to model transient ischemia-reperfusion and endovascular therapy, so this model is the most relevant.

Q.  Does the transient stroke model need to be the filament suture model, or can it be a different transient MCA occlusion model?
A.  As long as what you are proposing makes sense in the context of transient ischemia and reperfusion with endovascular therapy, then it would be considered to be appropriate and within the scope of this RFA. However, please keep it mind that the specific technique must be generalizable across sites. If it requires a particular expertise, then you should propose how this can be translated to the other network sites within the first year of the project period.

Q.  Is there any intent to standardize the transient ischemia model across sites?
A.   We expect all prospective sites to have already mastered the tMCAO model. It will be up to the coordinating center to make sure the protocol is consistent across research sites.

Q.   What are the variables (i.e. basic experiments mentioned above) that you would like to see tested before the adaptive design kicks in and eliminates weaker candidates?
A.   These will be decided by the Coordinating Center based on data analysis.

Q.  Is it expected that every site will use a different comorbidity model?
A.   A minimum of two sites will be required to perform the same set of experiments at all times. We hope to have a range of expertise in comorbidity models so that we can include several of these. Please include in the application all relevant information about which specific comorbidities you have experience working with.

Q.  Since at least two sites will need to use the same model, should we include in our proposal the models with which we have the most expertise?
A.  Yes, the specific models, co-morbidities, species, etc. with which a PI and/or group has expertise should be explicitly stated within the application. The reviewers will be considering this during their review of the research team.

Q.  When it comes to co-morbidities, how do we know which are the best to propose?
A.   Please propose all co-morbidities that are relevant to stroke and species that you have experience working with. You won’t necessarily be using all these models (you will work with the Coordinating Center to come up with the actual experimental plan), but such information will be extremely helpful to the reviewers.

Q.  Will additional aged mice be allowed beyond the normal allotment from the NIA colony or other sources?
A.  
We have not discussed this with NIA, but it is unlikely that special accommodations will be made for this network. If a lab is proposing to use aged animals, we expect them to have the capacity to perform these studies.

Q.  What does clinically relevant neuroimaging mean?
A.  
Clinically relevant neuroimaging would include any relevant technique that is used in human patients to assess stroke impact, recovery and outcome over time. For example, MRI would be desirable.

Q.  How rigorous does the neuroimaging study design need to be?
A.  
We realize that neuroimaging is expensive. Therefore, we cannot support techniques that are currently not used in the clinic. However, beyond proposing an appropriate technique, specific imaging parameters will be decided together with all sites and the coordinating center. Available funds will be allocated fairly based on these decisions.

Q.  How will intellectual property and publications be handled?
A.  
NINDS will not retain any intellectual property. The IP rights will belong to the applicant who is developing the intervention. Publications will have to include authors from all the testing sites as part of the network, but the order of the authors will reflect the lab from which the intervention comes from.

Q.  What is the plan for publishing positive or negative results?
A.   The coordinating center will take the lead on publishing all the network results at the end of the testing period, regardless of whether they are positive or negative.

Q.  Will future clinical trials automatically stem from successful participation in SPAN?
A.   No, you would still be required to apply through StrokeNet or some other clinical network.

C. Application and Review

Q.  Can I submit a multi-PI/multi-site application?
A.  
Multi-site applications are not encouraged for this program. Collaborations with co-investigators would be appropriate if there is a strong justification for why additional expertise may be necessary for the success of the project. It is critical that a single point of contact and project lead serve as the PI at each participating site. The program was designed around the idea of a single PI. If an applicant feels strongly that a Multi-PI is warranted, it would need to be carefully justified.

Q.  For multi-PI applications, will the 3-month minimum effort apply to each individual PI?
A.  As mentioned above, we really would like to discourage multi-PI applications for these RFAs. However, if a multi-PI collaboration is warranted and strongly justified, then we would expect both PIs to commit the requested 3 months of effort.

Q.  How would you view a coordinating center application from two partner sites, but with a single overall PI?
A.   We can award only one site with a single PI, who will be the point of contact. However, we recognize that it is unlikely that a single site will have all the expertise required for the Coordinating Center. Subcontracts for specific portions will be allowed, if they are justified and detailed in the application (in terms of resources, expertise, effort, etc.)

Q.   Are foreign sites or coordinating centers allowed?
A.   No. Only domestic institutions and PIs are eligible to take part in the SPAN network.

Q.  Do U01 and U24 applications need to be submitted separately or can they be part of the same package?
A.   These must be submitted separately and will be reviewed separately. Please remember that if you are awarded both, then you will only be allowed to accept one or the other. The Coordinating Center cannot also be a testing site to avoid the appearance of a conflict of interest.

Q.  If you have more than one neuroprotective intervention that you’d like to test, can they all be submitted in the same application?
A.  No. Each individual intervention will require its own application.

Q.  In terms of the budget, how much detail is needed beyond a regular budget justification section? This may be a little difficult to plan since we don’t necessarily know everything that we will be testing.
A.   The exact number of animals and budget allocation to each site will be determined by the Coordinating Center based on the experiments assigned. However, it is strongly encouraged to include an estimated sample size and an estimate of the budget required to perform all the proposed experiments for your specific intervention. You do not include your cost estimate for testing other sites’ interventions.

Q.  What is the approximate sample size you have in mind for each site? This will be relevant for the budget calculations.
A.   The sample size will be determined by the Coordinating Center and will be based on statistical analysis. As indicated below, you are encouraged to include your best estimate of the sample size required to demonstrate efficacy and for each of the comorbidities that are being proposed.

Q.  How much of the review will be based on the team and its ability to run a translational testing core? How much will be based on the neuroprotective intervention itself?
A.   Both of these considerations will be a major part of the review process. We want to have a team that is very strong and has the expertise to run a testing site. At the same time, we will also be looking to pick the six most promising interventions.

Q.  If I am a new investigator with no prior history of NIH funding, can I still submit an application?
A.   Yes, you are still welcome to apply. However, a major review criterion is the PI’s expertise and ability to manage and participate in a multi-site project, so prior experience and infrastructure is a definite plus.