Technical Assistance Webinar: Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Clinical High Risk for Psychosis Clinical Trial Network (U01 Clinical Trial Required)

Transcript

JONATHAN SABBAGH: Hello, and welcome to the technical assistance webinar for RFA-MH-24-150 or otherwise known as the Accelerating Medicines Partnership Schizophrenia, Clinical High Risk for Psychosis Clinical Trial Network. My name is Jonathan Sabbagh. I am a program officer at NIMH, and I will be taking you through our webinar today. We'll go over some background information, housekeeping notes. So this call is being recorded. The recording of the meeting and the content of the presentation will be available online at a later date. So if you are unable to watch the whole thing or if you have others that are interested, please let them know this will be made available soon. If you have questions, and we hope you do, throughout the webinar, please submit them via the chat. My colleague Suzanne Garcia will be monitoring the chat. And once we get to the open Q&A portion of the webinar, she will be reading out the questions to me. So the notice of funding opportunity, or NOFO, that we'll be discussing today, as I mentioned, is the AMP Schizophrenia or Accelerating Medicines Partnerships Schizophrenia, Clinical High Risk for Psychosis Clinical Trial Network, U01 Clinical Trial Required RFA. Please note that this is a cooperative agreement, and therefore there will be substantial involvement from NIMH staff and steering committee. The link to the funding opportunity is posted at the bottom of the slide. If you have not had a chance to review it, please do so when you have a chance. And also, one other note, please mute yourselves for the entirety of the webinar. The purpose of the webinar is to provide information about the notice of funding opportunity and also answer general questions. If you have specific application questions that you would like to discuss, please contact me via the email listed here, and I'll be happy to chat with you.

I'll go through a little bit of background for the NOFO. So early intervention is a key strategy for preventing psychosis onset and other adverse outcomes among individuals at clinical high risk. To make progress towards achieving the strategy, the AMP Schizophrenia initiative was launched back in 2020 to address challenges associated with target validation and drug development in this population. Most notably, challenges associated with identification of biomarkers for predicting progression, heterogeneous clinical outcomes, and differences in presentation. The drug development tools that are being generated by the AMP Schizophrenia consortium will hopefully be able to distinguish the clinical course of individuals with clinical high risk and predict psychosis outcomes. The purpose of this funding opportunity is to determine whether these tools, these biological, digital, cognitive, and clinical outcome measures developed in the AMP Schizophrenia observational study, are viable as drug development tools in Phase 2 clinical trials. A secondary goal of the funding opportunity is to determine if the biomarkers can act as their pharmacodynamic readouts of drug response and/or provide insights into the mechanisms underlying CHR or psychosis. The RFA will fund one clinical trial network to evaluate the utility of these tools in either one or two Proof of Principle clinical trials using compounds that are selected by the AMP Schizophrenia steering committee. And I'll go into a little more detail later on about what that entails.

The overview of the timeline is shown here. One other note, the letter of intent due date is September 17th. Although this letter of intent is optional, it's very helpful to NIMH for planning purposes, especially to our review branch staff. So we really encourage you to submit a letter of intent. It's very, very brief, very simple to put together, so if you can do it, please do. And one note about the timeline, just for planning purposes and the application, the earliest start date for the award will be July 2024. I'll now go through some general questions and answers. Some of these are generic for RFAs in general, and then some will be a bit more specific to this NOFO. And after the general question and answer session that I pose, and we'll have open questions where I'll hopefully be able to answer some of the questions that you put in the chat box. So as I'm going through these, please feel free to populate the chat with your questions, and we'll get to them during the open portion. So first general question's, will the RFA be reissued or submission dates added? And the answer is no. This is a single-issue RFA with one single receipt date. So there is no plan to reissue it or add submission dates. The question what are the budget caps? And although the budgets are not limited, they need to reflect the actual needs of the project. And I'll go into a little more detail on the next slide regarding that. And can prior approval be obtained to exceed the budget caps? The answer to that is no.

So related to the budget, are the set-aside amounts that are listed in the RFA for the full duration of the grant or just the first year? And the amount provided, which is up to $15 million total cost, is for the first year of the grant. Funds for subsequent years are contingent on funds being available and will be determined based on the trial protocol and other factors that we'll go into later in the webinar. Are there special page limits for the applications under this NOFO? The answer is no. Standard page limits for the U01 mechanism apply. So the research strategy section is limited to 12 pages. If you have any questions about the page limits or other formatting issues, please do visit the website listed here on grants.nih.gov. Are applications or components from non-US institutions allowable? And for this NOFO, the answer is no. Foreign institutions will not be eligible to apply, and foreign components are not allowed. For more details, you can see section three in eligible applicants header in the NOFO. Are appendices allowed? And the standard NIH policies regarding appendices are applicable here, so specifically, only the following types of documents are permitted in the appendices: blank data collection forms, blank survey forms, and blank questionnaire forms, sample lists of interview questions, and blank informed consent and assent forms. If you have letters of support, these should go in the application, not as part of an appendix.

So before applications will be sent out for review, they will be assessed for responsiveness. And the responsiveness criteria are listed here. So the following will be considered non-responsive to this NOFO, and the applications will not be sent out for review, and they will be withdrawn and sent back to the PI. So applications proposing a clinical trial network with fewer than 10 sites, applications proposing a clinical trial design with fewer than 100 participants, and applications that do not include a centralized site that serves administrative functions for the rest of the clinical sites will be deemed non-responsive. And these responsiveness criteria are listed under part two, section one of the NOFO. Should the PI propose to investigate specific pharmacological interventions in the application? And the answer to this is no. The compounds that will be used in the Proof of Principle trials will be selected by the AMP Schizophrenia steering committee. So the applicants do not need to propose specific compounds to be used in the trial. Can participants recruited for the Proof of Principle trial already be enrolled in another study? Once again, the answer is no. It's expected that co-enrollment is not going to occur for the full duration of the Proof of Principle trial. Will the clinical trial network be responsible for analyzing the data? And again, no, the raw data will be sent directly to the Clinical Trial Data Processing Analysis and Coordination Center or CT-DPACC for quality control and analysis of the data. The CT-DPACC will be funded under a companion RFA, which is listed here, MH-24-151. So the clinical sites will send the raw data directly to the CT-DPACC for processing.

So this is a question that I imagine many of you will have as you assemble your application because this is a unique funding opportunity wherein the study design, interventions selected, the outcome measures are all going to be chosen by the AMP Schizophrenia steering committee. What should the content of the application actually be? And although we can't give specific instructions about what you should put in the application, I will mention that it's really important in this NOFO to pay attention to the specific sections and bullet points listed in the application instructions, which is section four. Particularly under the approach section, there are a number of different plans that should be put together, as well as specific points that need to be attended to. And then, in section five, are the reviewer criteria that will be assessed, and those largely mirror section four but should also be examined to ensure that you're able to address every point that reviewers will be paying attention to. How will CHR status be evaluated in the Proof of Principle trials? So the awardee should anticipate using the Positive Symptoms and Diagnostic Criteria for the Comprehensive Assessment of At Risk Mental States, or the CAARMS, harmonized with the Structured Interview for Psychosis Risk Syndromes, or the SIPS, which collectively has been termed the PSYCHS, instrument to ascertain CHR status. And the PSYCHS instrument has been nicely explained in these two publications. The second of which is currently in medRxiv, but will be published in the next couple of weeks in Early Intervention in Psychiatry as well, so please look out for that. But if you have questions about the PSYCHS, these papers will help illuminate you. If the awardees do not have experience with the PSYCHS instrument, the AMP Schizophrenia steering committee will provide specific training to help.

So what type of expertise is optimal for the study team? And as noted here, it should be a multidisciplinary team that can cover expertise in the range of biological and clinical outcome measures that are currently being examined in the observational study. I highly encourage you, if you're not familiar with it, to look at the protocol on the AMP Schizophrenia website listed here. I'm not going to go into detail on them today, but it's important that the team that you assemble in your application is able to perform each of the different protocols and tasks, and measures that are currently being examined in this study. For the actual Proof of Principle trial, only a subset of the measures will be selected depending on which compound in the trial design. So this question and answer related to the regulatory processes involved in the trial. So firstly, who is responsible for filing the IND, or Investigational New Drug, application and registering the trial on clinicaltrials.gov? And the answer is that the PI of the U01 will be responsible for negotiating a legal agreement with the company providing the compound in conjunction with their institution, obviously. They'll be responsible for submitting the IND application to the FDA and registering the trial on clinicaltrials.gov. The details of how the PIs plan to complete these tasks should be included and spelled out in the regulatory plan component of the application. And more details about that can be found, again, in section four, the application instructions. Furthermore, applicants should anticipate needing to meet regulatory standards or an interventional trial. And most notably, part 11, compliance for electronic record management.

And last question, I believe, before we get to the open Q&A section is, what is the governance structure and decision-making process for the U01? And this is at the bottom you see here, spelled out in section six under the Cooperative Agreement Terms and Conditions. But briefly, the NIMH CHR steering committee will serve as the governing board for the clinical trial network, and this will consist of the PD or PI of the U01, The PDs or PIs of the CT-DPACC, project manager of CT-DPACC, the NIMH project scientist, and NIMH program officer and members of the NIMH executive committee. One of the roles of this NIMH CHR steering committee will be to participate in AMP Schizophrenia working groups that will ultimately develop a protocol for these trials. And again, please pay attention to all the criteria listed under section six there if you have more questions. So hopefully, we have some questions coming into the chat, but if not, please feel free to start typing them in. Again, I can't necessarily ask or answer any questions specific to your application. I'll be happy to handle those offline if you want to email me. But if you have general questions about the NOFO, I'm happy to take them now. Suzanne, do we have anything coming in?

SUZANNE GARCIA: Yeah, Jonathan, we have two. The first one is just a general administrative question. Will you be making the slides available to those on this call?

JONATHAN SABBAGH: The answer to that is yes. So both the recording and the slides will be made available. And the recording should be posted on a website that we can share after the call, or you can email me. And the slides, I'm happy to share via email after the webinar is over.

SUZANNE GARCIA: Great. Thank you. The second question, and our final one so far, is if the CT-DPACC is supposed to receive raw participant-level data directly from each of the sites in the network, how will the PHI be handled since it's a different funding mechanism?

JONATHAN SABBAGH: Yeah. That's a great question. And that's something that will be determined in conjunction with the PI of the CT-DPACC, the PI of the U01, and the NIMH CHR steering committee. Obviously, we're very sensitive to PHI needs that are required around this, so that's the question that we really can't answer yet, but depending on how the different teams want to structure and how NIMH can help facilitate that, we'll be able to determine it once the awards are made. Again, if you have any general questions, please do submit them in the chat. We'll give people a couple of minutes to digest and process some of the information that I went over and see if you have any other questions.

GREG FARBER: Jonathan, maybe if you allow, maybe I want to follow up on that PHI question.

JONATHAN SABBAGH: Please, please do. Thank you.

GREG FARBER: I do think that the NDA GUID is required for the awardees and all of their sites to use. So my suspicion is that the GUID will be the way that we'll end up managing the PHI. I don't think that it's at all likely that each site is going to be submitting name and identifying information to the coordinating center.

JONATHAN SABBAGH: Right. Absolutely. Yes. And that information is listed in the NOFO, so. Thank you for reminding me, Greg. Do we have any other questions coming in through the chat?

SUZANNE GARCIA: Yeah. So there was one that came in a little bit late. The question is, are those outside the United States applicable or able to apply towards this?

JONATHAN SABBAGH: Unfortunately, no. For this NOFO, foreign components are not permitted in any application, and foreign institutions are not allowed to apply. And again, we have plenty of time left in our webinar session. So I don't want to rush anyone to get out of here. Feel free to drop off if you don't have any other questions, but I will hang around and give people an opportunity to put more questions into the chat.

[silence]

JONATHAN SABBAGH: If there are no other questions, I think that's a good sign. It seems like everyone is pretty clear on what is needed to put in a competitive application. Again, if there are any specific questions, you want to ask about your application or advice you'd like to seek, I'm happy to either set up a call or answer questions via email, so please feel free to reach out. And we'll just give people one more minute to see if there's any other questions, and then I will assume that everyone is satisfied, and we'll sign off.

[silence]

SUZANNE GARCIA: Jonathan, there's one last question. How can people reach you later for additional questions?

JONATHAN SABBAGH: Excellent question. So if you have any questions about this NOFO that were not addressed in the webinar, please do send them to my email, jonathan.sabbagh@nih.gov. If you don't have time to write it down or remember it, it should be listed on the NIMH website as well, as well as on the specific funding opportunity, the NOFO, at the bottom of the page.

SUZANNE GARCIA: And one more question. Will the clinical trial research network have any role in data analysis?

JONATHAN SABBAGH: Any what data analysis?

SUZANNE GARCIA: Have a role in data analysis?

JONATHAN SABBAGH: No. So as I mentioned, the raw data will be sent directly to the CT-DPACC, which is the data processing analysis center, and they will perform the data analysis.

[silence]

JONATHAN SABBAGH: Again, I don't want to rush the closure of this. It looks like we have one more question.

SUZANNE GARCIA: That is, what is the motivation for researchers to be involved if no role in analysis?

JONATHAN SABBAGH: Sorry. I heard an echo there. The motivation of researchers to be involved in no role in analysis?

SUZANNE GARCIA: Yes. What is their motivation if they are not involved in the analysis?

JONATHAN SABBAGH: Well, hopefully, to assemble a great team that can put together a network capable of running a Proof of Principal clinical trial with a huge importance toward advancing the agenda in CHR, which is to validate these tools that are being developed critically in AMP Schizophrenia observational study. All the publications that will be put out from these trials will be a group effort with members of the U01 and the CT-DPACC as well. But Holly, if you want to answer that question more thoroughly, please go ahead.

SARAH H. LISANBY: Yes. Thank you. Well, first of all, Jonathan, thank you for this webinar and for your great answers to these questions. I agree with your comments. So it's not just about collecting the data and data analysis, but a data interpretation. We are seeking to support a very large collaborative network that would work very closely with the DPACC in order to collect, analyze, and then interpret and publish and disseminate information that will help us understand whether these tools are helpful in drug discovery for treatment of Clinical High Risk for Psychosis. And so, the scientific contributions will rely very heavily on the investigators who are participating in the research network. And we really do hope to cast a wide net and encourage anyone who is interested in contributing to this academic effort to please join us.

JONATHAN SABBAGH: Thank you, Holly. Well said.

SUZANNE GARCIA: Another question, Jonathan, is, given the probable inclusion of digital biomarkers, should these digital applications be regarded as medical devices [inaudible]?

JONATHAN SABBAGH: So I think the question was should the digital markers be regarded as medical devices from a regulatories perspective. And the answer to that is largely no. It really depends what the digital market is. But the digital markers that are being currently under study and that are likely to be studied in the Proof of Principle trials would not be considered as devices per the FDA and, therefore, should not need to be considered as such for regulatory purposes. But Holly, perhaps you can address that as well.

SARAH H. LISANBY: Yes. So I think the answer is it depends on what the marker is. And, of course, we really appreciate the participation of the FDA as part of this as a partner in this effort. And that through that partnership, they will advise us about questions like that. We do know that software is maybe considered a medical device, and so software, which is part of an algorithm. So if a biomarker involves a software as a medical device, then that could technically qualify as a device. But again, it really depends on what the specific measure is, and we will be working very closely with the FDA to have clarity on that question.

JONATHAN SABBAGH: Right. Thank you, Holly, for that extra context. Any other questions, Suzanne?

SUZANNE GARCIA: No, nothing else.

JONATHAN SABBAGH: Okay. Again, if you have specific questions, please, please, please reach out to me. I'm happy to jump on a call or answer via email. So thank you all for attending the webinar, and we look forward to seeing some wonderful applications from you soon. Take care. Bye-bye.