My name is Dr. Wendy Weber, and I'm the branch chief for clinical research at the National Center for Complementary and Integrative Health. We use a lot of protocols for many of our trials and ask for our investigators to submit those, and so that's why I was asked to give this lecture. I do want to give credit to Dr. Laura Lee Johnson who I know is one of the faculty for many of your courses. She used to give this lecture many years ago and transferred it over to me when I joined A.C.H. And I still heavily rely on her initial slides, so I like to give She used to give this lecture many years ago and transferred it over to me when I joined NCCIH. And I still heavily rely on her initial slides, so I'd like to give credit for that. So, what I'm going to talk about tonight are the -- to define the different parts of a protocol, and hopefully give you a really strong rationale as to why you want a very well-written protocol for any clinical study that you attempt to undertake. credit for that. So what I'm going to talk about tonight are the two define the different parts of a protocol and hopefully give you a really strong rationale as to why you want a very well written protocol for any clinical study that you attempt to undertake. And then also, to give you -- there's, at the very end, a number of different resources to help you in the design of these different protocols. Within the NIH Intramural Program, there are certain templates that are available. And I'm going to share with you a recent template for a protocol document that was just recently released for public comment from the FDA and NIH for trials that involve products that will be used in trials that are conducted under an IND or an IDE. And I'll tell you a little bit more about that as we get there. So, the question that -- especially people who are new to clinical trials, there is often a lot of confusion around the difference between what goes in the application versus what's in an actual protocol, versus how detailed the Manual of Operations and Procedures is. And so, there's -- particularly for first time people doing trials, they're like, "That's all in the application. That's exactly what I'm going to do." Well, in reality, most applications have page limits. And so, you only have a few pages to really succinctly describe what it is you're planning to do in that application and in that project. Whereas a protocol doesn't have a page limit and it really should be a very detailed discussion of exactly how everything is going to be done. In the case of a protocol, someone else should be able to pick it up and run the same study and get the same results, ideally. It should -- it adds to our ability to replicate trials if we have very well-documented and well-written protocols. Now, the difference between a protocol and a manual of operations and procedures is that -- what we sometimes call the MOP -- is that the MOP has even more detail. And so, for example, if you will be collecting blood samples in your trial, you may just describe what types of tubes are used to collect those blood, and that they'll be processed and shipped and where they'll be shipped to. Whereas in your Manual of Operations and Procedures, you'll detail specifically how much blood, how many of each tube. And not only that, but how each one is processed. If it needs to be spun in the centrifuge, how long it should be spun in the centrifuge, if it needs to be stored at specific temperatures, all of those details will be there. As well as the detailed process of how you ship any specimens that need to be shipped in the -- for the study protocol. So, it's the level of detail as to the difference between these different documents. And so, the question I often get is once people get past the idea that their application is not sufficient to describe what they're going to do for their study, and they get to the idea of a protocol and get comfortable with that, they start realizing that there are these two different documents. And the question is, "Do I really need both?" And the answer really depends on the -- on how large your study is, how many detailed procedures there are going to be. For many institutions, there are standard operating procedures, for example, of how patients with suicidality when they are depressed are managed. And there's a standard operating procedure of how that is done at a given institution. And rather than re-detail all of that out in a protocol, you can refer to the standard operating procedure and just file that in your MOP is what you can do. And so, depending on how many of those you have, it may make more sense to separate the documents, have a protocol that's kind of the streamlined, "This is what we do," and the MOP is absolutely every single detail to make sure that it's done step by step the way that it needs to bed done. Another time when it can be very useful to have both documents is when you're conducting a multi-site study, and one or more of your institutions requires that they use their template for protocol, a Manual of Operations and Procedures can really help to make sure that all of the sites are doing procedures the same way. So, whether it's the Manual of the Intervention Delivery for, like, cognitive behavioral therapy and step by step what is going to be done in the trial and how the intervention is going to be delivered. Those kinds of details don't always need to be in the protocol. They can be more detailed in the MOP. And then each institution can refer to a shared Manual of Operations and Procedures for the aspects that will be done the same across the different sites. So, this again, helps to ensure that there's fidelity of the intervention, that it's done same way across all sites. Another scenario where that's really helpful is if you're -- if each site is, for example, running a cytokine panel on blood samples and you want to make sure that everybody does it the same way, a very clear and detailed step by step process of an actual standard operating procedures of how that's going to be done and how that's shared across sites and how you're going to make sure that you have similar standards across sites, that can be done through the MOP as well. The key piece about having both is that whenever you update one document, you have to be sure to update the other document. There is a lot of overlap between these two. And so, you want to make sure that whenever you're making protocol changes, you're updating your Manual of Operating Procedures along with it, so that you don't run into discrepancies where if you don't follow your protocol, you essentially deviate from your protocol and you have to file it as a protocol deviation. Well, if you start off with the two documents telling you to do different things, you have set yourself up to no matter what, have a deviation from either your MOP or from your protocol, one way or the other. So, making sure that things agree is really important. So, the purpose of a protocol is to really give you an overall roadmap of how the study is going to be laid out and how it's going to be done. From the study design all the way through recruitment and randomization of participants if they're randomized, delivery of the intervention if you're delivering an intervention, how you're going to collect data from individuals, how you're going to then store that data, use that data, analyze that data, and report it in the end. So, it really is from beginning to end of your clinical study. And it really takes you to the next step of, "Okay. This is the five or six pages or maybe 12 pages I had to describe what I was going to do, and detail it all out as to exactly how I'm going to do this." You can often anticipate problems. So, if you realize that you need to do a fasting blood draw first thing, but you also need to get some other baseline measure on an individual and you have to decide which one needs to be done first. Do we want to give them -- you know, take our blood draw first or do we want to have them perform this really important lab measure that also needs to be done fasting? When can we feed them? Well, can we feed them in our clinical site as to where they're actually being seen and where the data's being collected, or do we have to take them to some other waiting area so they can have a snack before we ask them to fill out three hours of survey instruments. You can't come -- ask someone to come in fasting and then give them three hours of additional survey instruments to fill out without giving them an opportunity to eat. So, writing all of these different steps out really helps you in figuring out and identifying where the challenges are going to be. And it's really helpful to have one of your staff members or even -- I often hear the principal investigator will say, "Okay, I'm Patient 0, walk me through this. Let's act as if, 'Okay, what questionnaire do I fill out next? What piece do I next? Where do I need to go?'" Well, what if the lab that needs to do your EKGs is 30 minutes across town, and you were thinking you were going to do that as part of your first study visit when you have a whole bunch of other things you need to do in another site. Spelling this all out can really help you figure out the flow of the study and make sure that things happen in a way that can actually be done. And while you write that down on the protocol not until -- or sorry, you write that all in the application, it's not until you actually sit down and think about actually taking a patient through it all. Do you realize -- they need to be in two different places at once, or who is going to -- you know, this person is supposed to be blinded, and this task is going to un-blind them. And so, how are we going to collect that information and make sure that we're not unintentionally un-blinding our study staff and reducing the rigor of our studies. So, the other -- there's many purposes to the protocol. Another is to really make sure that everything is done the same way for all participants. And that's both the safeguard of the participants in the actual study, as well as to make sure that the data is collected the same way in all participants. I often get the example of blood pressure. If we have a participant who's running late, they walk in and the first thing you do is measure their blood pressure, and they have been stuck in traffic for an hour and a half and they saw an accident on their way in, and now you want to take their blood pressure. And if that's your primary outcome, whether or not blood pressure's reduced, that's probably not the best accurate -- and most accurate measure of what their resting blood pressure is. So, how long do you need to have them wait? How long do they need to rest? Can they talk on their cell phone while they're resting? Will that increase their blood pressure even more? So, there's a lot of different details, even though it's something as simple as blood pressure, if it's your primary outcome, you do need to specify the details of how you're going to collect that. Are they sitting? Are they standing? Are they laying down? There's a lot of different ways that you can collect something like -- as simple as blood pressure. So, the other nice thing about having this protocol all written out is it really facilitates communication among all of the different players that are involved in the clinical trial. So, you have your biostatistician involved, you have your funding agency potentially involved, your collaborators, the employees that you might be working with. If you're working with a funding agency that is an employer, for example, that's another group that you might be working with. And by laying this all out and kind of identifying your analytic plan and what the primary and secondary outcomes are going to be, you actually can get quite a head start on your manuscript preparation, because you've already detailed all of your methods in your protocol. And then you can just -- you can even do a methods paper about the protocol itself so you don't have to reference that and use so much of your space in your primary publication, talking about the study design itself. You can reference that in a separate publication. And you can even start making decisions about authorship and who -- what are the qualifications for authorship, those kinds of things we often see in protocols as well. So, I mentioned that there was something new. This is the something new. So, just about last week or so, March 17th, the NIH and the FDA put a notice out in the guide asking for public comment on a draft clinical trial protocol template that would be used for Phase 2 and Phase 3 IND or IDE studies. So, either substances that fall under the investigational new drug application and need to be conducted under an IND with the FDA's oversight, or device studies that are required to have the study conducted under an IDE, which is the Investigational Device Exception application. And so, this is open for public comment for a month. All of the screenshots I'm going to use for the table of contents for the protocol actually comes from this template. And if you use the link that's here about how to submit a response and -- from -- to get to the draft template, you'll see that these are available on the Office of Science Policy here at NIH for these Clinical Trial Protocol Template Documents. Also, there are the policies related to the Clinical Trial Definition for NIH, the Sharing Clinical Trial Information Policies, and Clinical Trial Enrollment tracking requirements for NIH. So, this is, as I said, something brand new, but it is something that I think you're going to see being used across NIH as a protocol template, and for the FDA as well for these IND/IDE type studies of Phase 2 and Phase 3 designs. So, what I plan to do next is to walk through some of the key elements of a protocol. I -- as you'll see, as I show you the screenshots of the table of contents, you'll see that the list is quite long of all of the elements that go in. One of the things you'll notice if you go to the site is that there's two documents there. One is a PDF that is the template with instructions in it, and the other is a fillable Word document that doesn't have the instructions so that you can really use it as template and create your own protocols, but there are instructions in the PDF version. As I mentioned, I'm only going to highlight a few of the really key areas. And what I'm going to try to do as well is kind of point out where the protocol would vary from a MOP. There's so much overlap in what's covered. I'm going to try to give you a few examples in each section around how a MOP might be different and what additional information you might find in the Manual of Operations and Procedures.