NIH All About Grants Podcast � Phase III Trials

Narrator:� From the National Institutes of Health in Bethesda, Maryland, this is "All About Grants."

Kosub: Hello, and welcome to another virtual edition of NIH's "All About Grants" podcast.� I'm your host, David Kosub, with the NIH's Office of Extramural Research.� And today we're going to be talking all about Phase 3 clinical trials, and what they mean here at NIH.� For those who are interested in learning about the other phases of our clinical trials, by all means, check out other information we have on our website.� But today, it's all about Phase 3. I'm glad to say we have two guests with us.� We have Dawn Corbett, Miss Dawn Corbett.� She is the NIH's Inclusion Policy Officer within the Office of Extramural Research, and we also have Dr. Christine Hunter; she is the acting director of the NIH's Office of Behavioral and Social Sciences Research.� So thank you both for being with us today.

Corbett:� Thanks, David.

Hunter:� Thank you.

Kosub:� Great. �So Dawn, I'm going to start with you.� What is a Phase 3 trial, anyway?� So set the foundation.

Dawn Corbett:� Sure.� Well, there's a few different definitions of a Phase 3 trial, but NIH actually has its own definition of what we call an NIH-defined Phase 3 clinical trial, and it's a bit unique.� You can find the full definition on our website, but essentially, what NIH defines as a Phase 3 trial is, a broadly-based perspective investigation that compares two or more interventions.� A Phase 3 trial often is aimed at generating evidence that may lead to a consideration in a change in health policy or standard of care.� So that's a really key component of the definition, is that evidence from a Phase 3 trial may lead to a change in the standard of care. What makes NIH's definition different than some other definitions you may have seen is that it's quite broad.� It includes not only drug studies, but it also includes device studies, behavioral interventions, epidemiological studies, community trials, etcetera.� So it's a lot broader than some of the other definitions of Phase 3.

David Kosub:� And what makes Phase 3 trials unique?� Or in other words, how are they similar, how are they different from other clinical trials?

Dawn Corbett:� I'll start by saying that Phase 3 trials are similar to earlier stage trials in a few ways; first in that they involved some kind of intervention.� And they are prospective, so they are looking at people going forward, rather than doing a retrospective study. Also, many Phase 3 trials are similar to other trials in that they're comparing one intervention against another intervention, or a placebo.� Now this isn't a criteria for all earlier stage trials, but it's pretty common.� But it is a characteristic of Phase 3 trials that they're comparing two or more interventions. So where they're really different -- there's a couple of places.� The first is, they tend to be larger than earlier stage trials.� And the reason for that is, the purpose is really to determine if the intervention works in the general population at risk.� So we're looking in a Phase 3 trial outside of a highly-controlled laboratory setting, and we need to have a sufficient sample size to represent a population at risk.� Then also, the sample size needs to be large enough so that it can detect a clinically significant effect. So they tend to be larger, although in some cases, they may be on the smaller side.� But they often have several hundreds, thousands of participants.� And then the real key difference between a Phase 3 trial and earlier stage trials is that the trial has the potential to provide evidence for a change in the standard of care.� So this is really the key of a Phase 3 trial which really sets it apart from earlier stage trials.

David Kosub:� Great.� You kind of touched on some of this, but maybe we can get a little bit more.� What should someone be thinking about if they're considering doing a Phase 3 trial, especially perhaps like in the application, as they're developing their application, what should they be thinking about?

Dawn Corbett:� Well, I'll start by saying it is important to get that determination right, and to understand if you're doing a Phase 3 trial or another phase of a trial, because it affects how you fill out your application form.� So specifically, in the PHS Human Subjects and Clinical Trials Information Form, there's some additional requirements for Phase 3 trials that are not required for earlier phase trials.� One of those places is in Section 2 of the form; there's an attachment for plans for inclusion of women and minorities.� And in that attachment, NIH-defined Phase 3 clinical trials will need to describe plans to conduct analyses by sex or gender, race and ethnicity.� And we have -- I'll put in a plug for a website that we have with a lot of information about those analyses which we call "valid analyses" on the grants.gov page -- sorry, grants.nih.gov page.� But we also have additional requirements for data and safety monitoring for Phase 3 trials.� So this is something when you're filling out the application, in Section 3, there is an attachment where you'll include your data and safety monitoring plan.� And then you'll be asked a question about whether or not you're using a data and safety monitoring board. So Phase 3 trials are generally required to have a data and safety monitoring board, so they would typically answer "yes" to that question, and then they would describe their monitoring procedures, and that data and safety monitoring plan.

David Kosub:� Since you plugged the website, I can also plug a great podcast that you were part of on valid and stratified analyses, a little bit more, too.� So you also mentioned standards of care a couple of times earlier on.� Can you tell us more about what's the role of Phase 3 trials in influencing standards of care?

Dawn Corbett:� Yeah, so Phase 3 trials are unique, because if successful, evidence from the trial mainly do a change in a standard of care, or even a change in health policy.� An example of this is for FDA-regulated drug trials.� The Phase 3 trial is usually the last step that's required before FDA approval of the drug, so you've tested for safety and efficacy, and you find preliminary efficacy.� Then you'll do a Phase 3 trial to see if it works in the general population.� And at that point, if successful, you would try to get FDA approval. But it's important to keep in mind that the trial being proposed should be providing the evidence that may change the standard of healthcare policy.� So if you're doing a trial where the potential to change that care may rely in additional research being conducted in the future, or it it's kind of far removed, you may not be doing a Phase 3 trial, and you may want to talk to your program officer about the appropriate phase.

Hunter: �So I agree with Dawn completely, of course.� But there's also the caveat that there's really no guarantee that a standard of care or policy will change from any study.� But in thinking about whether your studying Phase 3, you want to think about whether the data accumulated before the trial supports that it's moving in the direction that it could -- that the data from this Phase 3 trial could change healthcare policy or standard of care, and that the quality, rigor, things like generalizability, should be of a nature that it would support decision makers in making those changes and making new standards of care.� And I'll just say in the behavioral and social sciences, there isn't a regulatory body like the Federal Drug Administration.� So unlike for drugs and devices, in our field, we need to think about, would this provide sufficient evidence to inform other types of decision makers, whether that's groups like the U.S. Preventative Services Task Force, or the CDC's Community Guide, or disease organizations like the American Diabetes Association, or American Heart Association -- would the information provided lead to a change in the way that they approach publishing and distributing standards of care?

David Kosub:� Thanks for that.� Since, Christine, since you mentioned behavioral social sciences research, as you know, NIH has -- we support research across the gamut.� Are there any sort of considerations that -- as it relates to specific research areas?� Maybe even using behavioral social sciences research as a guide?

Hunter:� Honestly, there really aren't any substantive differences in thinking about behavior science versus other types of science, and what phase it is, other than the lack of regulatory pathway that I heard you mention.� But I think there is less familiarity on the part of researchers and research agencies, like at NIH, about how different behavioral trials fit, how to classify them.� So I think that can trip people up.� Dawn mentioned this, but it really warrants that advance discussion and consideration.� So there's agreement about what the phase of the trial is, and how that'll be classified long before you submit your grant.

David Kosub:� I see.� I see.� Well, since you mentioned submitting that application, after we've thought about this Phase 3, what's happening next?� It's going to go through peer review -- what are the peer reviewers going to be thinking about or looking at, or reviewing as it relates to these trials?

Dawn Corbett:� So peer review is going to look at Phase 3 applications much like they would look at all grant applications in doing their assessment.� But there are a couple of additional considerations for NIH-defined Phase 3 clinical trials.� First, peer review will be looking at plans for analyses by sex or gender, race, ethnicity, and that will be part of their consideration of whether or not inclusion is appropriate in the study.� Based on their evaluation, they may consider the application to be acceptable or unacceptable, and those with unacceptable plans must be resolved before they can be funded by NIH.� They'll also be looking at the data and safety monitoring; they look at this for all clinical trials.� But for Phase 3 clinical trials, they generally will need a data and safety monitoring board.� So that's also part of the review.� Reviewers will look at that and see if monitoring is adequate, and this will all be reflected in the score.

David Kosub:� And what about for those that get a good score, go all the way, get funded?� Now we're at the point of actually doing the trial and reporting back to NIH on the progress.� How should people be addressing that?

Dawn Corbett:� Yeah, so if your NIH Phase 3 trial is funded, you will have some additional things to report in your progress report.� So all NIH grants have to submit progress reports every year.� If you're doing an NIH-defined Phase 3 clinical trial, you'll also need to report progress on any analyses by sex or gender, race and ethnicity in your progress report.� So often early on in your trial, you may not have much to say in terms of those analyses; they may still be in progress, and that's fine.� But you should include a statement letting us know that they're in progress in every progress report, and give us updates.� Then once those analyses are complete, you'll include those analyses in a Project Outcomes section in your progress report, the RPPR. So the Project Outcomes section, if you're not familiar with it, it's a brief summary written in lay language that is actually made available to the public.� It includes results on your study.� So something to keep in mind is that included in those results should be any results of analyses by sex or gender, race and ethnicity.� And then we have one final reporting requirement for applicable clinical trials -- so applicable clinical trials are FTA-regulated drug and device studies.� They have an additional requirement if they're also NIH-defined Phase 3 clinical trials, to report the results of their analyses by sex or gender, race and ethnicity in clinicaltrials.gov.

David Kosub:� Definitely lots of things to be thinking about and keeping in mind, all the way from application, all the way through award. This has been a great opportunity to learn more about these ins and outs of the Phase 3 trial.� Are there any final thoughts?� I always like to leave some time for our guests to say anything that they haven't been able to say that's incredibly important about this particular issue.

Hunter:� Well, "incredibly important" is a high bar, but I would like to say that based on the things you've heard from Dawn about all the extra reporting and the significance of what a Phase 3 trial means in terms of data and safety monitoring and other important factors is, we just really strongly encourage researchers to engage their program officer at NIH early on about these issues, and discuss where do they see their trial following, why, and coming to agreement.� It's important for the application, it's important for peer review, and it's important for monitoring.� And you really want to have those things nailed down before you submit your application. So to help with that, on the Office of Behavioral and Social Science Research website, under Research Resources, we have created a decision support tool.� And it really kind of outlines features to consider in determining if your trial is a Phase 2 or a Phase 3 clinical trial.� And it's really -- the tool is just to help guide those discussions.� It reviews kind of what the distinguishing features mean, so the change in standard of care and health policy, and then outlines features to consider.� So that includes how to think about selection of a comparison condition, purpose in relation to establishing efficacy and effectiveness, and then thinking through number of participants and sites, and the duration of the trial, and how those decisions might or might not affect the determination of what phase the trial is.� So that conversation with your program officer in advance is just super-important to kind of smooth sailing through the granting process.

David Kosub:� Well, thank you very much.� We definitely cleared that high bar, and smooth sailing.� Well, I appreciate that, Christine.� And Dawn, this has been a great opportunity to learn more about Phase 3 trials, how NIH is thinking about them, considering them.� I definitely encourage everyone to check out the information that's available on the NIH's grant site, as well as what Christine just mentioned on the Office of Behavioral and Social Science's Research's website, their decision tool -- check it out. This has been David Kosub with the Office of Extramural Research, "All About Grants."� Thank you.