MI HILLEFORS: Okay. Well, thank you very much. And welcome, everyone, to this technical assistance webinar. It is for the RFA-MH-24-120 Precision Mental Health: Develop Tools to Inform Treatment Selection in Depression, the UG3/UH3 Clinical Trial Optional. And we are delighted to have you here. As a general information, as Dr. King already mentioned, this call is being recorded. The recording of the meeting and the content of the presentation will be posted at a later date. If you have questions, please submit them via the Zoom chat. And Dr. King will monitor the Zoom chat, and we will try to get to them at the end of the presentation, after the presentation. I know that we also have petitioner and IMH staff on the technical assistance webinar today. So they will hopefully be able to help us if there are some specific questions.
MI HILLEFORS: So first, I would like to go over a little bit about the Notice of Funding Opportunity (NOFO). For some of you, you will be familiar, probably, with the term Funding Opportunity Announcement, FOA. NOFO is the term that has replaced FOA. So you will hear us refer to NOFO. You may also hear me refer to RFA, which is Request for Applications, and that is a type of NOFO. So to avoid some confusion here during the presentation. So the NOFO that we are talking about is the Precision Mental Health: Develop Tools to Inform Treatment Selection in Depression. This is a phased award that requires the completion of milestones in order to progress from the first phase, the UG3, to the second phase, the UH3. And to note for everyone is that this is a cooperative agreement. And that means that in difference from kind of regular parent research grants, there is a substantial involvement from NIMH staff, as well as implementing a steering committee to guide the project.
MI HILLEFORS: The purpose of this webinar is to provide information about the NOFO and answer general questions. Please note that we cannot provide feedback about specific planned applications or research projects that you have in mind. If you want to discuss specific applications or aims or the applicability for this NOFO, please contact me. You can send me an email at email@example.com. I am also listed at the scientific research contact in the NOFO, so you will find my information contact there. As a background to the Level IV, there are several treatment options for depression, as we know. These include the drugs, medications, psychosocial interventions, digital therapeutics, brain stimulation methods, et cetera. However, we also know that the selecting the right treatment still relies largely on trial and error. Each treatment may require three months or more to determine if it’s efficacious for a specific individual, and about 40% of the patients that we treat do not fully recover, even after a year of treatment. There will be one or more of available antidepressant treatments. There is an urgent need for tools that integrate the pretreatment measures to predict whether a depressed individual will have differential therapeutic response to a specific treatment and can help aid clinicians in selecting among the multiple available treatments.
MI HILLEFORS: The one goal of this NOFO is to create a pipeline to support initial tests of validation and visibility of objective, easy-to-use, and widely accessible tools for predicting response to depression treatments at the level of the individual. So we are really looking at something where the clinician can use to make a treatment selection for an individual patient. And looking at it, it can really look from social environmental determinants, and going down to value market tools, digital assessments and patient in the loop, continuous learning, and being able to stratify patients for treatment response. So specific to this NOFO, I want to mention about the Phased Award Mechanism, the UG3/UH3. So for the cooperative agreement, the two different phases, you may be familiar with the phased awards in other NIMH and NIH funding opportunities. For example, our clinical trial pipeline, they used an R61/R33 phased award.
MI HILLEFORS: So for this, the total project duration cannot be more than five years. And the duty three phase is between one to two years. They cannot exceed two years. We do not specify the length of the UH3, but together the two phases cannot exceed five years. NIH intend to issue about 10 awards in 2024, and it will be used with set-aside by the NIMH. We have a limited budget. So the Phase I UG3 phase is limited to $500,000 in direct cost per year. And the UH3, the larger prospective clinical trials, are limited up to one and a half million dollars in indirect costs per year. The timeline for this phased award is SSL up to five years. The Phase I, UG3 phase, which is really preliminary studies looking at, for example, retrospective secondary allows this fast fail pilot studies. The goal is to de risk efficacy trials by demonstrating sufficient signal for clinical utility. And we will be using kind of Rigor/Reproducibility, /Generalizability, and evaluate those as go/no-go criteria. The Phase II, the second phase, the UH3, is a larger-scale biomarker/tool-stratified clinical trials. The prospective trial to test the efficacy of the biomarker or the tool that has been proposed against standard-of-care decision making. And the goal is really to be able to select between at least two antidepressant treatments.
MI HILLEFORS: I will add, the important thing is that this NOFO is not about developing the interventions themselves. It is really about the biomarker, the tool by signature, and we are looking at already well-established treatments. I will be coming to that as a question. Future plans of this NOFO, which is not part of this initiative, which is not part of the NOFO, is that once we have established and identified biomarkers as tools, we are hoping that we would maybe be able to establish a point of care technology research network to support rapid development or commercialization and implementation in the real world conditions. That is not something that we currently have allocation money for, and it’s something that is more aspirational rather than that we know will happen. But I wanted to mention where are we going past the current NOFO.
MI HILLEFORS: The timeline for the FY 24, specifically, and there is a letter of intent due September 18th this year, 2023. Letter of intents are optional. They are not required, but it is very helpful to the NiMH for planning purpose, both to understand the workload, as well as for review planning. So we welcome if applicants send us letter of intent, but it is not required. More information is in the NOFO. The key dates to keep in mind, the NOFO is currently written for two cycles. One in 2023 and one for 2024. Currently, we have set aside for 2023 for the first round. The second round will be depending on available funds, but the data and key dates are listed in the NOFO. The important thing is that the due date for applications is about 18th, 2023, this fall. We anticipate that the review, the scientific merit review, will take place in March 2024. It will go to the NIH Advisory Council for review on the Main Council 2024. And the earliest start date would be next summer. That is all in the best-case scenario.
MI HILLEFORS: So that is really the quick overview of the NOFO. We already received many questions. So we wanted to reassemble a lot of general questions that we have and thought we will start by going over them. And then we’ll be happy to take more questions and try to answer them to our best ability. And Dr. King will, as I said, monitor in the Zoom chat box to see what questions we are getting. But please, you may want to hold off to see if we already have answered some of them in our following slides here. So one question there was is, will the RFA be re-issued or submission dates added? And at this point, we are not planning to reissue the RFA. They have the two submission dates, we are not planning adding additional, and I would say the second submission date will depend on available funds. What are the budget caps? We have listed the maximum annual direct cost for the UG3 phase, $500,000. For the maximum annual direct cost for the UH3 phase, the second phase is one and a half million.
MI HILLEFORS: Can prior approval be obtained to exceed the budget caps? Short and correct answer is no. Are the set-aside amounts that are provided in the RFA for the full duration of the grant or only for the first year? So the set-asides are for the first year of the grants, and NIMH intends to commit $5 million total in FY 2024 to fund up to 10 awards. Are there special page limits for applications under this NOFO? And the answer is no. Standard page limits apply and the research strategy section is limited to 12 pages. You can find information on the web about how to apply for page limits. Are applications from non-U.S. institutions allowable. And the answer is yes, foreign institutions are eligible to apply. You can find more information about that in the Section III under information about eligible applicants. Are appendices allowed? We are following the NIH policy regarding appendices. You can find that information in the notice, OD-17-098. Specifically, only these appendices are permitted. You can have blank data collection forms, blank survey forms, blank questionnaire forms, simple list of interview questions, and blank informed consent forms. Please note that the letter of support or not considered an appendix and can be submitted as a part of the application.
MI HILLEFORS: Will applications be assessed for responsiveness before being reviewed, and what are the responsiveness criteria? And yes, all applications will be assessed for responsiveness prior to peer review. So this is part of– as this is a request for application, an RFA, and very specific criteria outlined in the NOFO for what would be considered non responsive. I would really advise all applicants or anyone who is considering putting together an application under this RFA to read those in the borders. We have copied them here. I will not read them all, but they’re all outlined in the NOFO. Because if your application meets any of these criteria on non responsive, the application will be administratively withdrawn by NIMH prior to review and it will not go to peer review. So this is not a case that– we never like to do that, but we want to make sure that all applications are responsive to the NOFO before sending them to peer review.
MI HILLEFORS: So this is really a look at Part 2, Section I about what would be nonresponsive criteria. Is it allowable to propose a clinical trial? Yes. It’s optional. It is allowable, but not required. We will accept applications that propose studies that meet the definition of clinical trial if the prospective assignment to intervention and assessment of outcomes serve the purpose of deriving or validating a biomarker or signature that can accurately predict depression treatment response. The trials focused on determination of efficacy and development of candidate therapeutics as the primary goal are not considered responsive to the NOFA and would not be reviewed. As I mentioned, the goal is really to look at the biomarker tool signature or biomarker. But not at the developing the intervention themselves. You can find more information about NIH definition of clinical trial, and NIMH funding of clinical trials on our website. What is considered well established treatment? So for the purpose of this NOFO, well-established treatment for depression is defined as those that are FDA approved, for drugs and devices, or for non-regulated interventions, such as the various psychosocial or cognitive behavioral therapies, that are considered well-validated, widely used, recommended for treatment in treatment guidelines. I would say that we are talking really about evidence-based interventions that have shown efficacy.
MI HILLEFORS: What are the expectations for data sharing for this NOFO? The same as NIMH may require for all projects that are funded under this NOFO. That they will deposit biannually all data generated by the project into the NIMH Data Archive, also known as NDA. You can find more information about NIMH data sharing on this web link. And as I said, we will be sharing these slides afterwards, so you can have other links through the slides. There is also many references in the NOFO to the NMH data archive. So if you’re not familiar with it, I really recommend that you check out the NIMH data sharing policy. What type of expertise is optimal for a study team? We are expecting that they will be multidisciplinary teams that should cover the expertise in areas relevant to the proposed project. This can be included, but it’s not limited to biomarker and signature development, clinical expertise relevant for the clinical populations of interest, including clinical trial designs, computational, statistical, bioinformatics analysis, experience with use and development of detection method technology, bio sample, data or tissue source standardization, and biological, behavioral, physiological expertise in the depression condition or conditions under investigation.
MI HILLEFORS: So a broad range of expertise. It really needs to be relevant to the project that you are proposing and cover all the areas that are needed in order to conduct a project. Importantly, we expecting there will be a required multiple principal investigators, MPIs, for the projects. And all MPIs should be involved in the development of the research plan and the coordination and execution of the project. We anticipate that we that all the MPIs should be part of writing the application and kind of not just jumping in at the end and providing a short section or something. It needs to be a whole picture where the whole team is a part of the process. This is essential in order for the projects, as they go forward, and being conducted for successful projects. So those are some of the general questions that we have received leading up to this technical assistance webinar. We are happy to take more questions now in the chat. If you have questions after the webinar or you want to follow up more on any of these questions, please feel free to email myself at firstname.lastname@example.org or Dr. Erin King at email@example.com and we will be happy to get back to you and try to answer the question to all of the stability.
ERIN KING: Mi, we have a few questions in the chat if you want me to go ahead and read those.
MI HILLEFORS: I probably could stop sharing here and we’ll move to so you can see. So yes, please go ahead.
ERIN KING: Sure. So the first question is how do we handle indirect costs of funds allocated to the multiple PI sites?
MI HILLEFORS: Well, so we are looking at the applicant and the institution. So even if you have subcontracts, that would be for the applicant institution to deal with, and ultimately, we are looking at what would be the indirect costs in the budget that submitted to the NIMH.
BRUCE WEXLER: That was my question, Mi, and I’ve already discussed it with our grants office here. So just for example, I got on board very quickly with the multiple PI, and have arranged– we got four institutions prepared to work on this together with complementary expertise. So if we have, for example, a $100,000 budget at one of the institutions, and we have to take out– and let’s say, my institution is a host one who gets a $500,000 grant, we have to pay the $100,000 out of our $500,000 direct to the subcontract at one of our sites. And pay $67,000 more for their indirect costs out of our direct cost. And that doesn’t seem to be the intent of a $500,000 direct budget cost, that we’d end up paying, if we have three institutions, we’ll pay $200,000 of that in an indirect costs, and really only have $300,000 for direct costs. There used to be a mechanism of multiple, linked R01s that came in as a project together, and then each of them would have–just the indirects would have been separated, so.
MI HILLEFORS: So this is a very good question. And I have two answers. One is that no, this is not a collaborative R01. So that does limit and it becomes one budget. For specific questions, I would advise you to contact Terri Jarosik, who is listed as the financial grants management contact in the NOFO, and Erin, maybe you can put in the chat. Actually, I can put her information in there. So Terri Jarosik. So for direct financial and budget questions, I would advise you that you could ask her about that. But otherwise, yes. The circumstances usually would be addressed with collaborative R01s are not part of it.
BRUCE WEXLER: Because we are planning the Phase I and Phase II together, obviously. I mean, that’s what we had thought. So I wanted everybody to be involved from the get-go. So we put together our plan together. It’s possible with a $1.5 million budget, but with 500,000, as I said, 40% of it will go out of the direct cost to go to indirects for the collaborators. Correct?
MI HILLEFORS: I cannot answer that question, but I do understand. I do understand where you are coming from. My advice is that depends on what your project will be, your budget, and what sites. And if you have direct questions, I do see that Nick Gaiano, who is the head of the review branch is had his hand up.
NICK GAIANO: Thanks, Mi. So this is really the purview of grants management. And Terri’s in the office next to me, although she’s not here right now. But this came up recently, and I absolutely encourage you to confirm that I have this straight. But we recently saw some things that looked like they were over the budget cap. But it turns out that consortium in direct costs, I do not believe count against the budget cap listed in the NOFO. And it’s for very much the reasons you’re describing. It seems like it would be sort of nonsensical and a penalty to the investigators. So yeah, please, of course, double check, I wouldn’t march off and assume that’s correct. But I am 95% sure that that’s correct.
BRUCE WEXLER: Very encouraging. Thanks.
MI HILLEFORS: Thank you. Thank you, Nick. That’s very helpful. And yes, please contact Terri Jarosik, who is the head of our grants management branch.
ERIN KING: So we have a few more questions in the chat. The next one is would the PI be able to maintain ESI status if receiving the UG3/UH3 grant?
MI HILLEFORS: So I will have to check on that. Okay, Nick.
NICK GAIANO: Yeah, I saw that question in the chat, and I looked it up. I think the answer is no. It’s a substantial enough award. So there’s a list. You can go look online. There’s a huge list, and they tend to be smaller rewards, of what you can get and retain ESI status, but UG3, that’s not on there. It tends to it tends to relate to what the size of the award is as far as whether that gets rid of ESI status or not.
MI HILLEFORS: And so I would say that it’s the size, and the intention of this is certainly larger than many R01s. So it’s really the application itself will most likely not receive an ESI status, because we are asking for multi PIs. Unless all PIs are ESIs, the application does not get the ESI status. So it’s something to discuss, but we certainly would like to see early stage investigators or more junior investigators involved in the projects, because we really like to have the diversity and the range of the investigative pool.
ERIN KING: Great. The next question is, can Phase I projects be 18 months, or do they have to be 12 or 24 months?
MI HILLEFORS: They can be in the maximum two years. It is up to the applicant to decide how you want to divide up the five years, with the first phase not being more than two years.
ERIN KING: The next question is, are EMA symptom assessments with or without physiological measures considered signatures for prediction?
MI HILLEFORS: I could not answer that question, because it would depend on kind of how it’s put together. And so I don’t have the answer for that.
ERIN KING: Sure. So in addition to testing–
MI HILLEFORS: So for whoever put in that question, if you want to have more, we can certainly set up a time, talk more, once you have your aims and what it is and have a more in-depth discussion with NIMH subject matter experts to see if it is a good fit for their RFA.
ERIN KING: Sorry about that, Mi. In addition to testing univariate predictors of differential response, is it considered fair game to use machine learning to generate precision treatment rules to predict the optimal intervention for a given treatment?
MI HILLEFORS: So we are looking at the broad range of tools that can make biomarkers, and I think we have listed a lot of the different– whether it’s imaging, computational, blood-based markers, clinical markers for being able to help ultimately help recognition, making a selection between at least two antidepressant treatments. So it really depends on how you are planning on using the proposed algorithm as a biomarker.
ERIN KING: Okay. Another question asking if primary care and secondary care are both allowable, especially if they include the source as a variable in the prediction equations?
MI HILLEFORS: I am not sure I really understood that question between primary care and secondary care here.
STEVE HOLLAND: Yeah, that would be me, Steve Holland. And secondary care, most folks are seeking treatment. Primary care folks are not necessarily seeking treatment, but they may happen to be depressed. And there’s emerging evidence that most folks who are depressed don’t seek treatment. And so you may have different biomarkers, different prediction equations for those two different settings.
MI HILLEFORS: It will be up to the applicant to decide in what population, what setting, what is the most likelihood that your biomarker would be of utility to a clinician. And also depending on what fits to what type of studies that you can do and conduct under this NOFO.
ERIN KING: Okay. It looks like the last question in the chat is someone mentioning that they have strong preliminary result and they’re trying to decide whether to finish up analyses and write up for publication. And if the publication submission would strengthen the application for this NOFO, or if the spirit of the award is such that this wouldn’t strengthen the application.
MI HILLEFORS: That is not something I could answer. I think it depends on what you believe you need to do to make the case for the tool and the rationale for studying and validating, assessing the tool in the study here. So I cannot answer whether to publish or not publish or whether it will strengthen or not strengthen your application.
ERIN KING: I don’t see any additional questions in the chat unless I’m missing any, if anyone else has questions, feel free to unmute and ask them.
MI HILLEFORS: Yes, I do see Dr. Lisanby.
SARAH H. LISANBY: Hi. So thank you for the presentation. I want to go back to a few of the prior questions. First of all, about machine learning. Absolutely, we expect innovation in terms of data science approaches, and so if that is relevant in terms of your prediction algorithm, we absolutely are looking for innovative data science approaches that might include AI, ML, et cetera. Regarding the question about publishing, I mean, this is going to peer review. Think like your peer reviewers. The more evidence that you are findings have passed peer review may be influential in terms of understanding the quality of the project that you’re proposing.
MI HILLEFORS: Thank you. For those of you who may not be familiar, Dr. Lisanby is the director of the Division of Translational Research and really has been the initiator of this NOFO, so you have the best information possible here. I would like, Just before I turn to any other question, is really recommend that you read the NOFO very carefully. There’s a lot of information in it. There’s also really specific– I would recommend for applicants to read the Section 5, the instructions to reviewers. Because that has a lot of information. We will be asking your peers to evaluate and assess when they review the applications. And if that information is not part of your application, reviewers will not be able to evaluate it. So you can receive a lot of information there in what you should include in an application. So that is my kind of advice to all potential applicants or interested parties. We are happy to answer more questions after. If you want to have more input once you decided that you want to apply and you have aims, we are happy to find time to give more input and guidance on the NOFO and the process, as well as input on your aims, if that is appropriate, or as appropriate. Well, I do not see any more questions, Erin. And with that, I want to thank– first of all, I’d like to thank Dr. Erin King for setting up the technical webinar and for preparing everything for today and for her work on the NOFO. I also want to thank both the Nick Gaiano and Dr. Holly Lisanby for helping answering the questions today. And I wish everyone good luck.
Thank you, Mi.