Webinar: NIH’s Definition of a Clinical Trial

Transcript

PROGRAM FACILITATOR: Good morning to those joining online. We still have people joining the room but we're going to go ahead and get started.

Welcome to NIH's Definition of a Clinical Trial presented by Dr. Aileen Schulte of the National Institute of Mental Health.

Just a couple housekeeping notes on top. Everyone who is participating has entered in listen‑only mode. So your cameras and microphones are off. If you have questions, we're using the Q&A feature in Zoom. So please enter any questions into the Q&A box. Some of the questions will be entered during the talk by our Q&A moderators and other questions, we'll wait until the end of Dr. Schulte's presentation.

We're making a recording of this webinar, and we'll make that available through NIMH. So they'll be sent out, or if you want to specifically get one, please reach out to us.

If you have any technical difficulties hearing or viewing in the Zoom call, please put these in the Q&A box and we can work to fix those issues, or you can also, in real time, send an email to us at this email at the bottom, nimh@mn‑e.com.

Okay. So welcome. I'm going to turn it over to Dr. Mesfin Bekalu for introductions.

DR. MESFIN BEKALU: Thank you. Good morning, good afternoon, good evening, depending on where you are. I'm Mesfin Bekalu. I'm a program officer in the Center at the National Institutes of Mental Health.

Thank you for joining us today for this webinar. This webinar session is part of the Capacity Building webinar series hosted by the Center for Global Mental Health Research at the National Institute of Mental Health.

The webinar series, which was started in 2022, covered a variety of topics, including training mechanisms for graduate students and post‑docs in global research, submission and peer review of NIH grant applications, grants management, pre and post‑doc work, writing successful grant applications, human subjects protection, data and monitoring and professional considerations in NIH funded research and others which are all available on our website.

Today's webinar is on another important topic, which is NIH Definition of a Clinical Trial. Dr. Aileen Schulte, who is a scientific review officer at the National Institute of Mental Health, will provide us with an overview of NIH's clinical trial classifications focusing on mental health research in a global context.

After her presentation, and during the Q&A, Dr. Schulte will be joined by Dr. Nick Gaiano, who is a chief officer at the branch of the National Institutes of Mental Health, and Dr. Jasenka Borzan, who is a scientific review officer at the National Institute of Mental Health.

With this, I will now turn the mic to Dr. Schulte.

DR. AILEEN SCHULTE: Thank you for the introduction, Mesfin. Thanks to our technical support team. Let me just start sharing my slides here.

Thank you to colleagues who will be helping with the Q&A. I assume everyone can see my slides now, correct?

Thank you. Good morning, good afternoon, good evening, whatever applies to you. Thanks to all who are joining today as well. Yes, my name is Aileen Schulte. I am a scientific review officer in the National Institutes of Mental Health. I typically work with mental health services research. I organize the Standing Study Section, SRV, Mental Health Study Service section. Some of you may have seen my name in that context.

And today, as mentioned, what we were going to do is discuss the NIH clinical trial definitions and the overall classification systems with a specific focus on implementation studies which are of interest to NIMH's Center for Global Mental Health Research.

So the first thing to note as I will be discussing this is as in the highlight here. We're talking about the NIH definition of a clinical trial. It is quite possible that the NIH definition of a clinical trial is not the same term that you used in another context. It's not the way you would refer to a clinical trial in another context, that is.

So you may, for example, think that a clinical trial must include clinical outcomes or it must involve a clinical sample or it must involve randomization or a comparator group. None of these things are true under the NIH definition.

It is definitely the case that the ‑‑ sorry ‑‑ the NIH definition of a clinical trial is a very broad definition, much broader than the typical clinical trial definition. This includes, as you can see maybe with the little blue circles here ‑‑ sorry if that font is too small ‑‑ but it includes pilot trials, for example. It includes mechanistic trials that do not include a clinical outcome.

It also includes basic experimental studies involving human subjects known as BESH Trials, B‑E‑S‑H, which simply involve experimental manipulation. These are defined as clinical trials under the NIH classification system.

These could just be simple lab experiments on social, psychological concepts or imaging studies where the experimental manipulation is exposing participants to either smiling faces or frowning faces, just a very transient exposure to an experimental manipulation may qualify the study as a CT under the NIH definition.

So I'm not going to go into great detail about the BESH studies because that's not of interest to you, but I think it is important to understand for applicants such as yourselves that if these types of studies are considered clinical trials under the NIH definition, then it is likely that investigators such as yourselves, who are interacting in clinical settings in lower or middle‑income countries could likely meet such definitions as well.

Okay. So please keep in mind, as we move forward, that determining the clinical trial status of your research is fundamental to submitting a viable application to the NIH. And that is because of the related considerations on this slide.

As you probably know, when you submit to the NIH, you have to pick a Notice of Funding opportunity, which defines how applications can be reviewed, where they're reviewed and all sorts of things about the award itself.

And, specifically, clinical trials must be submitted to Notices of Funding opportunities that have review criteria specific to clinical trials; and also if an application is funded, then it may be required that there would be reporting to clinicaltrials.gov, required clinical training, monitoring, et cetera.

So because the Notice of Funding opportunity defines the expectations throughout the award, then you need to make sure that your research is appropriately defined in terms of its clinical trial status in order to meet the appropriate requirements. That's fundamental.

So how do you determine the clinical trial status? There are specific questions that you must answer when completing your application. The answers to these will determine the clinical trial status of your application. And also what Notice of Funding opportunity may apply to.

So going through these one by one, number one, does the study involve human participants? Number two, are the participants prospectively assigned to an intervention or to an experimental manipulation? Number three, is the study designed to evaluate the effect of the intervention on participants? Number four, is the effect that will be evaluated a health‑related, biomedical or behavioral outcome?

So I will go through these in greater detail in later slides, but first, let's just consider the implications of the four questions and the definition.

There we go. Okay. So if yes to our four questions, the study is considered a clinical trial. Clinical trials may only be submitted to Notices of Funding opportunities that accept CTs such as clinical trial required or clinical trial optional.

You will see those phrases in the title of the Notice of Funding opportunity, in parentheses, at the end of the title. Clinical trial applications may not be submitted to Notices of Funding opportunities that do not accept clinical trials, and those have the label of clinical trial not allowed in parentheses at the end of the funding opportunity announcement title.

So I should note for K Awards or career development awards, these categories are expanded to include independent clinical trials required or independent clinical trials not allowed, which has to do with whether or not the research is conducted as part of another project such as perhaps under a mentor's funded project.

So for those mechanisms, K‑1, K‑23, et cetera, there's added complexity for those, but the same logic applies in terms of the four questions, as we will discuss.

Okay. And importantly, if you indicate that your application is not a clinical trial and the content of your application indicates that it is a clinical trial, the application cannot be funded if submitted to a NOFO that does not accept clinical trials and it must be withdrawn when NIH staff determine that it contains a clinical trial. That is very important for you to understand. We do not like the situation when this happens.

We would prefer not to return any applications. But as I mentioned, the application is not viable if it has clinical trial content and it is submitted to Notice of Funding opportunity that does not accept clinical trials.

So it would be best to return it and have you resubmit it somewhere where it is a viable application.

Sometimes my slides don't want to advance. Okay. So here we go. We will go through each of the four clinical trials questions. First, does the study involve human participants?

You may say, well, my IRB says that my study is exempt. That is not part of the definition. It still contains human subjects, human participants. Is considered HSR research. That would be a yes to question one.

It's also important to understand that if you say you are working with deidentified data, that may be the case for some members on the team, but if any member of the team has the ability to deidentify the data, then that is also a case of the study having human participants and you need to say yes to question one.

So, for example, if you have a community partner who is contributing data and that person is on your research team and that person can identify subjects, then that is a yes to question one.

I would say in general we don't see a lot of confusion on this point. I'm not going to spend a lot of time on question one. There are a lot of resources available to you. I've cited a few here just about NIH's rules about human subjects research in general. So you may refer to them.

Question two can get a little complicated. And this is perhaps where investigators had the greatest difficulty with how expansive the definition is. So are the participants prospectively assigned to an intervention or experimental manipulation?

So this question equates an intervention that is an attempt to improve a physical or mental condition with any type of experimental manipulation. As I referred to earlier, this includes basic experimental studies with human subjects, or the BESH trials that I mentioned earlier.

Now, prospectively assigned, again, that is something that's a very broad definition. It's not necessarily the specific scientific concept that you might apply here.

Prospectively assigned simply means it is decided in advance that the persons will experience either the intervention or the manipulation. It means decided by the researchers that the person will have this experience. It does not mean that they're randomized; rather, it means that researchers are exposing participants to something that they would not have experienced otherwise if they had not been in a study. Yes, that's a very broad definition.

So what I often tell people about question two is that you should not really think about any of these terms in red here as scientific concepts, but you really need to think about them more in terms of the protection of human subjects.

Ultimately, it comes down to what control and what responsibility do the researchers have for what the participants experience. And again it's important to think about this as a very broad definition all around. More detail about this.

So, for example, as I said, it does not matter if the subjects are randomized or not randomized. It could be a convenience sample. That is still prospective assignment. Any number of experimental groups would meet the definition here. So one group's designs meets the definition of prospective assignment. Does not matter if it's a clinical or nonclinical population. If you're only interacting with providers and you're providing them with some training or something to that effect, that meets the definition of perspective assignment.

In terms of what is an intervention or what is a manipulation. Again, this is a very broad definition. So any kind of training, any kind of education, anti‑stigma programs, family education, caregiver training, et cetera. Any sort of app that you give to participants. Any sort of clinical decision support that you add to a clinical setting.

As I mentioned earlier, simple experimental tasks for imaging tasks are also considered a "yes" under this definition. So certainly interacting in clinical settings is something that you have to consider as being under this category here.

Moving on to question three. Is the study designed to evaluate the effect of the intervention on participants? So given that the intervention could be an intervention in a traditional sense or experimental manipulation, then you also have to have a broad definition of the effect of that intervention. So effect does not mean effectiveness, as in efficacy versus effectiveness.

Any sort of effect that would be anticipated from the manipulation in question two is essentially a yes to question three. And so an effect is anything that could attributed or expected from that intervention or manipulation. That could include any change in knowledge or attitude, such as it's an anti‑stigma campaign, changes in stigma, any intent to change one's behavior such as intent to adhere to treatment.

This can include an effect on research participants as individuals or include an effect on an organization. So, for example, if your intervention is meant to increase rates of screening or treatment and engagement, then those things are effects, that would be a yes under question two. Again, it does not have to be a clinical outcome, per se. So what's the effect or outcome measured; is it related to the measure or manipulation?

Question four, is the effect that will be evaluated a health‑related biomedical or behavorial outcome? Typically, if questions one to three are yes, question four is usually a yes as well. Again, things that are related to knowledge or attitudes or learning about any health‑related concept, yes, that is a health‑related biomedical outcome. Provider behavior is a health‑related behavioral outcome. Intent to change one's behavior, treatment attendance and engagement all those things qualify here.

Behavioral outcomes are very broadly defined and include all of these things related to, as I said, participant's intent to engage in treatment or anything related to how providers do their jobs.

Okay. So I thought it would be useful ‑‑ how are we doing on time? Kind of okay. All right. So I thought it would be useful to go through a few case studies.

The NIH Office of Extramural Research has provided a number of case studies to illustrate how this policy may be applied in some examples of NIH research.

It's best to think of these case studies as an extension of the policy. There are dozens of them available on this website listed here. Just one quick example, Case 4B, the study involves the recruitment of research participants with disease X. ‑‑ very general here ‑‑ to receive a chronic disease management program. It is designed to assess usability and to determine the maximum tolerated dose of the chronic disease program, for example, how many in‑person and telemedicine visits would lead to adequate adherence.

I know this is very general, but just to give you a sense in answering the four questions here. So does the study involve human participants? Yes. The study involves human participants with disease X. Number two, are the participants prospectively assigned? Yes. The participants are prospectively assigned to receive an intervention, the chronic disease management program.

Is the study designed to evaluate the effect of the intervention?
Yes. The study is designed to determine the maximum tolerated dose of the program to obtain adequate adherence.

Finally, is the effect being evaluated health‑related? Yes. Tolerable intensity and adequate adherence of the intervention is a health‑related outcome.

That's pretty straightforward. It is a pilot study. Maybe that's a surprise that this makes it a clinical trial, but as you can see all of the answers here are yes under the NIH definition.

Another example, case number 23, study involves recruitment of physicians who will be randomly assigned to use a new app or an existing app, which cues directed interviewing techniques.

The study is designed to determine whether the new app is better than the existing app at assisting physicians in identifying families in need of social service support. The number of community service referrals will be measured.

So quickly, does the study involve human participants? Yes. It actually involves both physicians and families as human participants because you have how the physicians are using the app, collecting data on that, and then you have the families who will be ‑‑ let's see ‑‑ referred to social support or not. So there's data on that.

Are they prospectively assigned? Yes, the app itself is the intervention.

Is the study designed to evaluate the effect of the intervention?
Yes. The study is designed to evaluate the effect of intervening on physicians and to see whether or not social service support, if there's uptake of that by the families.

Then, finally, is the effect being evaluated a health‑related, biomedical, or behavioral outcome? Yes. The number of referrals is a health‑related outcome. Case study No. 20 is on the website that we'll share, that is also an example of how training providers can lead to a definition of clinical trial.

It's not moving. There we go. Couple more. So case No. 27, the study involves recruitment of parents to participate in focus groups to discuss topics related to parental self‑efficacy and positive parenting behaviors. It is designed to gather information needed to develop an intervention to promote parental self‑efficacy and positive parenting behaviors.

So they're gathering data to help inform an intervention. Is that a clinical trial? So there are human participants. The parents will be providing data in the focus group. Yes to question one. Are the participants prospectively assigned to an intervention or an experimental intervention? No, because the focus group is not an intervention. Group‑based intervention in the same context would be a yes, but simply collecting data about how people feel about parenting is simply a measurement.

Under the definition for question two there is a distinction between measurement and intervention. Given there's a no to question two here, the study would not be a clinical trial because it has to be a yes to all four in order to be a clinical trial.

Case number 36A, here's an interesting issue related to the standard clinical care given in a setting. The investigators conduct a longitudinal study of patients with schizophrenia. Their physicians as part of their standard clinical care prescribe antipsychotic medication. The investigators conduct an imaging session before starting treatment, that is, the medication. And they repeat imaging four to six weeks later. Is that a clinical trial?

Of course the study involves human participants. So that's a question to one. For question two, are they prospectively assigned to an intervention? No, not in this context because it was stated that the antipsychotic medications are given as part of clinical care; that is, the doctors made the decision about what the treatment would be, what the medication would be, what the dosage would be. So that is not part of a prospective approved research protocol. So that's a no to question two. The study is not a clinical trial.

Now, hypothetically, if the researchers had been involved in the decision about medication or dosage, this would be a yes to question two. And then the other, question three and four, would have to be answered as well. There's a specific case study on the website that you could look at, case study 36B.

But in general, if the researchers are simply observing the clinical care that is offered in any setting, that is a no to question two. Okay. So please keep in mind there are a number of resources that you can consider as you're putting your application together. You may want to look at them very carefully. So NIH has a clinical trial decision tool that can help you walk you through those four questions. There are the case studies that are available on the NIH clinical trials website. I also threw in the link to BESH if you're interested in that.

And importantly, you may want to talk to an NIH program officer before you submit to make sure you are answering the four questions properly.

So with that, I don't know how many ‑‑ if we have questions in the Q&A, but I would like to welcome my colleagues.

We have Mesfin, who finely did my introduction, and we have my colleague Jasenka Borzan, who is the NIMH referral officer, and we have Nick Gaiano, who is the review chief at NIMH. And I'm having problems with my screen here trying to see you. Hi, Nick.

DR. NICK GAIANO: Excellent work, Aileen, this is an important topic. We've not gotten a barrage but a steady stream of questions, some of which I think it might be valuable for you to address to the group at large. Of course, I'll also let Jasenka chime in.

But a very recent question which I think is an important point ‑‑ I'll try to zip through this but this is from an anonymous attendee.

Isn't the purpose of clinicaltrials.gov to host a space where people can search out studies that may benefit them with the inclusion of BESH trials, for example, in the NIH definition of clinical trial. These scientifically lay people are going to have a significantly harder time finding studies that may have direct benefit to them. For example, ALS patients may find and sign up for an observational study that includes them. The point is, to avoid harming the person a clinical trial was meant to help, will the NIH develop a page that is meant to house those studies that are only considered a clinical trial by NIH?

I think it might be good just to spend a little time, I don't know, discussing the philosophy if you can or if you know behind the NIH definition and how that can lead to confusion in the community. I'm not sure, but I think that's important.

DR. AILEEN SCHULTE: I agree that is important. It is probably a better question for the Office of Extramural Research, and I think you could think about clinicaltrials.gov as being that kind of resource, and I think that's important.

Whether or not there would be changes to clinicaltrials.gov to make it more user friendly, I think that could be thought of as a work in progress. But I also think there were other issues that I mentioned early on about the importance of the clinical trial designations.

It's also about monitoring human subject research as it occurs. So that, I think, for a lot of reasons has led to this broad definition. I don't know if Jasenka or Nick want to add anything to that.

DR. JASENKA BORZAN: I think that was a really good answer, Aileen. I think part of it is NIH has the responsibility to monitor both human subject protections over time, and I think that probably in part led to the broader definition of clinical trials and also a responsibility to ensure that taxpayer money spent that's being towards clinical trials has certain outcomes.

So the monitoring in part is really to make sure that, for the investment that's being made towards clinical trials, that there are outcomes that are measurable over time. I think that's in terms of the idea of the reporting in clinicaltrials.gov, there are multiple reasons for that, one of which is for people to find clinical studies but also for purposes of reporting and being transparent in how NIH is spending money for clinical studies.

DR. AILEEN SCHULTE: Yes, I agree. I agree. I think Nick and Jasenka, you might be writing answers to specific questions.

DR. NICK GAIANO: One person asked, can you apply from foreign countries? That's a pretty straightforward answer. The answer is yes, if the initiative indicates there's not an issue with that. You can find that under eligibility criteria.

For the most part, our initiatives do permit application from foreign institutions but it is good to double‑check that because on occasion ‑‑ and we had an example of this recently ‑‑ there may be situations where something from a foreign institution is for some reason prohibited and that can lead to challenges. And if something comes in from a foreign institution or foreign component, on the rare case the initiative doesn't permit it, it will have to be withdrawn.

There is one question I wanted to post: How does NIMH currently track its NIH‑defined clinical trials portfolio past and present in the context with helping with decision‑making?

DR. AILEEN SCHULTE: Again, I don't know if I can answer that. I think, first of all, what we're talking about is the NIH definition of a clinical trial. So NIMH is one of 27 institutes and centers that has a specific focus.

The policy here is broader than NIMH, for sure. We do certainly have an Office of Science Policy that tracks ‑‑ they report to Congress. They answer questions from the public about NIMH investments in various areas. So there is a tracking process going on. It's not part of my daily job, so I don't feel like I can answer that.

DR. NICK GAIANO: Some of these questions are maybe sort of airing to the general group regarding where responsibility lies. I'm sorry I put you on the spot with some of these where they are beyond the scope of what we have any real control over.

DR. AILEEN SCHULTE: I see a question ‑‑ just opened the Q&A box, I was going to respond to the first question here. So screening for something like depression, would that be a behavior?

So it's hard to answer that question without knowing the full context. So, for example, very often, in screening studies, what you see is the researchers are training clinical providers to be better at screening. So they might have an app or they might have some sort of clinical protocol that they're introducing in the setting.

So in that sense, certainly screening, like training providers to screen and then evaluating whether or not they screen, that's clearly a clinical trial.

In another context, for example, if you are evaluating whether one screener is better than another, that's really more of a measurement study. So instead of comparing the clinical outcomes of who was referred, who was not referred, if you are just looking at maybe the psychometric differences between two different screeners, that would be a no to question two.

So it's really important to think about the broader context in terms of the four questions. So it's very difficult to say if screening for suicide/depression, what have you, in and of itself is a yes to question two.

DR. NICK GAIANO: There's a specific question from one of the case studies that might be worth looking at it, one from 23. You can navigate these.

DR. AILEEN SCHULTE: They're asking about a case study that I didn't mention. Let's see. The study involves recruitment of patients with disease X who are receiving one of three standard therapies as part of their clinical care. It is designed to affect the relative effectiveness of the therapies by monitoring survival rates using medical records over a few years. If the research study is about ancillary strategies to support care delivery but the clinical side is choosing how to operationalize those strategies and the care that is delivered is at the discretion of the clinical site and the provider, not the study, not the research team, that would not be a clinical trial.

That would be a no to question two if the researchers have no control over what the care delivery is. That's also assuming that there isn't some other type of training going on from the research team to the providers.

But, yes, it is the case that simply observing the standard of clinical care in a setting is essentially a no to question two. I don't know, Nick, Jasenka, if you had anything to add to that.

DR. JASENKA BORZAN: I think you answered it quite well. Maybe a general statement about standards of care and how that plays into consideration of an intervention, if you could comment a little bit more about that, maybe. It seems like there's a few questions that relate to that question.

So if they're simply monitoring standard of care of patients and they're not introducing any experimental manipulations for this particular study, then it would not be considered a clinical trial because there's nothing ‑‑ as Aileen was mentioning ‑‑ there's no manipulation being done by the research team for that particular study; they're simply observing participants over time.

And although the outcome measures could be clinical in nature, if those outcome measures are already part of standard care; in other words, the experimenters, the researchers didn't introduce them, then it's not a clinical trial.

DR. AILEEN SCHULTE: Yeah, absolutely. We're getting a fair number of questions. I see one here for case study number 23, which I shared with you.

So hypothetically, if they didn't measure actual referrals and stopped at identification of families, would it still be a clinical trial?

DR. NICK GAIANO: Did you want to go back to that slide maybe, just for the group? It's up to you.

DR. AILEEN SCHULTE: I could.

DR. NICK GAIANO: Or not.

DR. AILEEN SCHULTE: I'm trying. No, no. There we go. So it's hard to imagine ‑‑ so they just identify families, like, for what purpose, I guess my question would be. So this is the one. So the physicians are basically given an app that will help them identify families in means of social support and the number of community service referrals will be measured.

So the app is the yes to question two. The number of community service referrals is the yes to question three. If they don't measure referrals, okay, potentially, I guess, that could be a no to question three, but what are they measuring?

I wouldn't be able to give you an answer to that unless we have another last sentence there. So after the families are identified, what happens?

And then the question is, is that measurement a result of the app that was training the physicians? So again, it depends, but it is possible that that could be a no if they didn't track referrals.

DR. JASENKA BORZAN: I would add that it depends what the app is actually asking the participants. If the physicians are using some type of either behavioral measures or other answers that are being provided in the app to identify people who are in need of social service support and how that changes over time, that could potentially still constitute a clinical trial, because the information being entered into the app is really kind of the outcome that they're observing, and they're observing changes over time in that regard. So it depends on how the app is designed.

In the case studies for NIH, typically what they talk about in terms of apps, if the application is simply asking subjects to comment on how easy it was to use or basically the functionality of the application itself, then it's not considered a clinical trial because the actual purpose of the application is not being tested for the purposes of the study.

So in terms of designing new apps and things like that, so feasibility and applicability of the app is not considered a clinical trial. If the app is being put to use and the data from what the subjects are entering over time is being used by the providers to make certain decisions, then it could potentially be a clinical trial.

DR. AILEEN SCHULTE: Yes, absolutely. I see a question here about implementation science. So the study is prompting a cite to introduce a new standard of clinical care but the only research procedures are interviews and surveys.

I guess the question is why. So what I would do here is I would go back to ‑‑ so, yes, very often in implementation science you are interacting with providers and encouraging them to do clinical practice in a different way, right? To oversimplify things.

So to go back to this slide, it's an intervention/manipulation, if you are providing training, if the research team is providing training. So that's a yes to question two. That goes with the apps, clinical decision to support, anything that the research team is providing to the providers that they did not already have. Very broad definition there.

But then the question is, essentially, about surveys, interviews with the providers.

So question three is, does the study evaluate the effect of the intervention on participants? So evaluating the effect of the intervention can be about their knowledge, their attitude, their willingness to do a certain procedure. All of those can be measured with a survey or interview. So that could be a yes to question three.

Again, it's important to know the whole study design to get a sense of this, but very often we see these implementation science studies where training is provided to providers by the research team and then the research team tests whether or not that training was effective. This is a clinical trial. Please understand that's a clinical trial under the NIH definition.

Do we have other questions?

I'm scanning very quickly. We answered 14. That's pretty good. So we have a question about retrospective or observational studies.

That is a very, very broad category. Retrospective could mean that you're looking at, say, clinical data collected by others and you're reviewing that. That goes back to my comment about question one that ‑‑ trying to get the slides to move ‑‑ if no one on the research team can identify the research participants, that would be a no to question one, which would mean the whole study is not a clinical trial.

In terms of observational, we were just discussing that in terms of, say, the research team is observing what is occurring in a clinical setting instead of trying to manipulate it. So, for example, let's say you're doing a domestic study in the U.S. where you're observing how, say, collaborative care, coordinated specialty care, something like that, is being implemented in a county or a state. The research team has no control over that. That decision was made by policymakers.

The actual roll‑out is being conducted by providers or their supervisors. In that sense, that's purely observational. That's a no to question two. I hope that answers that question.

All right. So we have about eight minutes left. If you can type quickly, you could do another question.

DR. JASENKA BORZAN: There's a follow‑up question on the use of a broad definition of NIH clinical trials. And in particular, the question is how the expansion to BESH for the NIH clinical trial helps good monitoring of human subjects research. Wouldn't it create a burden to diverting monitoring resources from actual clinical trials?

So I'll let you answer as well, Aileen, but my take on this question is that BESH studies can potentially be studies that pose risks to human participants as well, even though they're not clinical trials. Sorry, they are clinical trials. So BESH are a type of clinical trial. I apologize.

And because they can pose certain risks to human subjects, it is important that NIH monitors these studies just as a full clinical trial that is not focused just on basic experimental studies. Basic experimental studies really just implies that the study is focused on understanding certain underlying mechanisms or fundamental processes that are in place rather than being focused on potential treatments or clinical implementation of new interventions or things like that.

So it's really more focused on basic understanding and fundamental mechanisms without specific processes or products in mind. That's the definition of BESH. But because the protection of human subjects is equally important in those studies, even though there's no particular process or product in mind, NIH is responsible to monitor them accordingly as well.

DR. AILEEN SCHULTE: Yes, I think that's absolutely true, Jasenka, and you're the BESH expert, as I tell everyone.

So I'm reading the question here, and I guess the question is, wouldn't it create a burden to monitor these additional clinical trials?

Burden on whom, exactly? I'm not sure. So, for example, on the NIMH side, you have program officers who may have to do extra work, but those are different program officers in different areas of science.

In terms of burden on investigators, as Jasenka said, there's risk involved. So it is utmost important to make sure that that's managed appropriately.

Can BESH trials also be also classified as a basic NIMH project as opposed to applied projects? I don't ‑‑

DR. JASENKA BORZAN: The short answer would be no. But it depends. I'm not sure what the person is asking exactly. Basic in the sense that there's no specific process or product in mind. In other words, the intention is not that they're developing a new therapy for something, for example. So in that sense it can be considered a more basic study. But we have to go by the definition that's provided by NIH for BESH. We shouldn't be changing wording in that.

DR. AILEEN SCHULTE: Yes, that's our take home message. You need to be aware what NIH expectations are, what these definitions are and figure out how your proposed research fits within that.

No one is telling you have to do research a different way. This is about classifying and defining the research that you are doing and submitting it properly.

Nick, did you have something you wanted to add to that?

DR. NICK GAIANO No.

DR. AILEEN SCHULTE: Okay. Do we have any more questions?

DR. MESFIN BEKALU: I don't see any more questions.

PROGRAM FACILITATOR: As a reminder to everyone as we're wrapping up, a recording will be made available to attendees as well.

DR. MESFIN BEKALU: Right. I think our time is ‑‑ we have a couple of minutes, but I don't see any more questions.

Thank you so much, Aileen, for this wonderful and highly informative presentation, and Nick and Jason in your participation for the Q&A.

And thank you for joining us today. As mentioned, a recording will be available. So for now I wish you all a good time.

DR. AILEEN SCHULTE: Thank you. Thank you, Mesfin, and thank you, everybody. Great questions. Have a good day.