Megan Columbus: ���� Welcome to another episode of All About Grants. Today we're going to be talking about understanding the definition of a clinical trial and what that means for you.� I have with me today, Dr. Michael Lauer, who is the Deputy Director for Extramural Research for NIH.� Welcome.

Dr. Michael Lauer: ��� Thank you. Great to be here.

Megan Columbus: ���� So NIH is implementing a number of new policies for clinical trials, including clinical trial specific funding opportunity announcements, clinical trial specific review criteria, expanded registration and reporting for all NIH clinical trials and clinicaltrials.gov, et cetera.� Can you talk to us a little bit about why these changes are happening?

Dr. Michael Lauer: ��� Sure. So these changes have been long in coming. They've been coming for years.� And I would say that there are two major concerns that have been brought forward.� One is that a substantial number of trials that we fund don't see their main results published in a timely way.� In other words, we're giving money to scientists who then conduct experiments on people.� But then the results of those experiments are not reported out, they're not reported out in a journal, or they're not reported out in clinical trials.gov within a year or two of completion.� And this has been a source of major concern.� The second major issue is metadata, or high level agency wide data, that the agency needs in order for it to be able to function as an effective steward.� We spend about three billion dollars a year on trials.� Last year the GAO issued a report that said the NIH is not really doing a good job of collecting data across the entire agency so that it can be an effective steward of those trials.� And so those two things together, a better stewardship of trials and ensuring the trials get reported, have led to this many, many years long effort to improve our clinical trial oversight system.�

Megan Columbus: ���� And so that improvement really relies upon having a solid definition of a clinical trial.� And I know that in 2014 that changed.� Can you talk to us a little bit about the definition?

Dr. Michael Lauer: ��� Yes, absolutely.� If you're going to have a better policy about something, you have to know what the something is.� And you're absolutely right.� That was one of the very first things that happened.� So back in October of 2014, NIH issued a revised definition of a trial.� Essentially, a trial, from NIH's point of view, is a research study that involves human subjects where there is some kind of prospectively assigned intervention, and the purpose of that study is to see whether or not that intervention modifies a biomedical or behavioral outcome.� So we want to know, is there an intervention that is being prospectively assigned by the scientific project itself?� And is the purpose of the study to see whether or not that intervention leads to a change in some kind of biomedical or behavioral outcome.

Megan Columbus: ���� So that definition is very broad.� I assume that's intentional.� Was there community input when this change happened?

Dr. Michael Lauer: ��� Yes.� So the definition is broad.� This includes everything from, say, a physiologic study where you want to see whether certain types of, for example, autonomic nervous system blockade affects cardiac responses to stress�that would be almost like a basic science kind of project�to a phase III pivotal trial to see whether or not a certain kind of drug prevents major clinical events.� So this broad definition was intentional.� Back in November of 2014, we issued an RFI and we requested comments from the community.� We received over 240 comments.� These came from individuals, organizations, as well as very large professional societies that represent a very large swath of scientists and stakeholders.� And we did hear comments saying that the scope of our proposed policy was too broad, that our definition was too broad.� We also heard the opposite.� We also heard that there were people who thought that our definition was too narrow and that we should be including a wider swath of studies.

Megan Columbus: ���� Many of the studies that under the new definition, or the 2014 definition, we would now consider to be clinical trials don't focus on clinical endpoints.� Why are we folding those into the definition as well?

Dr. Michael Lauer: ��� That's a great question.� It turns out, when we've taken a hard look at our portfolio, most of the trials that we fund do not focus on standard hard clinical endpoints.� So think about, let's say, a heart attack trial that looks at preventing heart attacks or strokes or premature death.� That actually represents the minority.� Most of the trials that we fund focus on physiologic endpoints, biochemical endpoints, behavioral endpoints.� In a way, this reflects the nature of the portfolio of the NIH.� Now there were people who suggested that these kinds of studies should not be included in our reporting policy.� And we explicitly addressed that when we released our policy last year.� Essentially we said we disagreed with that.� And the reason why we disagreed with that was that there's an imperative for transparency, and there's also an ethical obligation to participants.� There's an ethical obligation to participants to assure them that people know about the studies that they're participating in, the fact that the studies actually exist, and also, that the results of the studies will become generally known and we'll give to science.� And so, we argued that that ethical obligation to participants, and the imperative for public transparency, is no different whether we're talking about a largescale pivotal treatment clinical trial, or a smaller clinical trial that's focusing on biological mechanisms.

Megan Columbus: ���� But when I think of basic research, or basic science, I don't think of clinical trials at all.

Dr. Michael Lauer: ��� I know, it's kind of interesting.� Some people have said, �Well, basic science is the opposite of trials.�� Now, if you go into clinicaltrials.gov, which is our national database of clinical trials, there's a field which is called primary purpose.� So the person who is registering the trial in the case, what is the primary purpose of this trial?� Is it treatment?� Is it diagnosis?� Is it screening?� Is it health services?� And it turns out that one of the preset selections that you can pick is basic science.� So I recently did a search where I looked for interventional studies in which the primary purpose was basic science, and I got over 1,600 entries.� Something like 1,640 entries.� And then just to make sure that this is for real, I also checked to see what proportion of those studies involve healthy volunteers.� Because you might expect that basic science studies might be more likely to involve healthy volunteers.� Eleven hundred of them involved healthy volunteers.� And if you actually look at those studies, they look and feel and smell exactly like a basic science project.� So yes, there are such things as basic science trials.� This is not a new idea.

Megan Columbus: ���� And so, the distinguishing factors for those would be there's an intervention and they're prospectively assigned?

Dr. Michael Lauer: ��� There's some kind of prospectively assigned intervention and the purpose of the study is to see how that intervention modifies a biomedical behavioral outcome.

Megan Columbus: ���� And what about observational studies?

Dr. Michael Lauer: ��� So right now, this set of policies only applies to trials.� We can think of trials as experiments in which there's some kind of prospective intervention.� It's a prospective intervention coming from the scientist, and the purpose of the prospective intervention is to modify a biomedical or behavioral outcome.� Many studies, both basic science as well as clinical research studies, are observational.� That is, the scientist is not doing any kind of prospective assignment, but they're making a measurement or they're watching something happen over time.� These policies do not cover observational studies, and I think that's an important thing for people to know.

Megan Columbus: ���� Understanding whether or not your research meets the definition of a clinical trial matters because now there will be funding opportunity announcements that people will have to use for applications submitted as of January 25, 2018 and beyond that will very clearly either state that clinical trials are required, or clinical trials not allowed, or some combination of both.� There will be institute specific funding announcements that will be issued, as usual.� But what about the parent announcements?� What will happen with those?

Dr. Michael Lauer: ��� Yes.� So all the current parent announcements will no longer allow clinical trials.� There will be some new parent announcements that will allow clinical trials, and the specifics will depend upon the discipline.� Some of the institutes will be joining certain parent announcements specifically for clinical trials.� Some of them, for example, may be parent announcements to bring in clinical trials that focus on mechanistic or physiologic endpoints.� But that's something that will be determined by each individual IC.� So that's why it's very important for people to look to see what kinds of funding opportunity announcements would be most appropriate for the study that they want to do.

Megan Columbus: ���� I know one of the questions that keeps coming up is what does this mean for peer review, for my clinical trial application?� If I didn't think of my study as being a clinical trial before, now that NIH considers it a clinical trial, does that change what happens in peer review?

Dr. Michael Lauer: ��� For the most part, the answer is no.� The most important thing is that a proposal should be reviewed by a group of peers who have the right expertise.� And we are going to make absolutely sure that that continues to happen.� In many cases, studies will be reviewed by the exact same study sections that would have seen them before.� Now they're going to be clinical trial applications, but nonetheless it will be the same group of peers, the same group of experts because that's the most appropriate thing to do.� We have heard concerns that certain kinds of studies that are more appropriate for a basic science study section will now be reviewed by a study section that looks at phase III or IV trials.� That's not going to happen.� That would be inappropriate.� The opposite, by the way, wouldn't be right either, for a phase III trial to be reviewed by a basic science study section.

Megan Columbus: ���� Another concern that we've heard is about administrative burden.� Does the benefits outweigh the burdens for this effort?

Dr. Michael Lauer:���� So I think one way we can think about this is that what we're asking people to do is tell us about the methods of their study.� That�s the registration part, and also, the information that's being requested on the application.� And tell us about the results of their study.� That's the final results reporting.� These are integral to the process of science itself.� So as we said in our policy document last year, we don't see this as a burden.� We recognize that there's additional work, but the work that we're talking about is describing your methods and describing your results, and these are integral components of the scientific method.� We also pointed out in the policy document last year that we want to be able to help investigators meet their ethical obligations to participants, to make sure that studies are properly registered and results are reported out.� And so, we see that as being something that will build up trust in the overall enterprise and therefore benefit everybody, including scientists.

Megan Columbus: ���� What about the good clinical practice training?� Is that a burden?� How much time does it take?

Dr. Michael Lauer: ��� So this typically takes a few hours.� There are many options that are available.� There are options that are available online.� Some are offered by NIH.� Some are offered by outside institutions.� There are GCP, or good clinical practice courses, that are specifically targeted to certain types of audiences.� But the typical length of this is a few hours.

Megan Columbus: ���� The other concern I hear is how do NIH's new policies for reporting relate to the very involved requirements that have to do with the FDA regulations and applicable trials and those things.

Dr. Michael Lauer: ��� Right.� Trials that involves FDA regulated products�and NIH does find some trials that involve FDA regulated projects�FDA regulations come to bear just like they do now.� Most of the trials that we fund do not involve FDA regulated projects.� So the types of FDA regulations that people think about, like applying for an IND or applying for an IDE, don't apply.� All we're asking for is that people register their trials in clinicaltrials.gov and report out their results.

Dr. Michael Lauer: ��� Thank you.

Megan Columbus: ���� From NIH and OER, this is All About Grants.

Megan Columbus: ���� We have lots of resources available to help people navigate the definition of a clinical trial and understand what the new clinical trial policies mean.� You can get to them by searching �NIH clinical trial requirements� in your favorite search engine.� Thank you for joining us, Dr. Lauer.

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