Hi. I'm Anne Casper and I'm going to talk to you about study documents used in clinical trials. I first want to share a little bit of background about myself. I have 18 years of experience in an academic coordinating center and five years as a clinic coordinator prior to that. My experience has been mainly in post-marketing trials in the US. However, I have done some trials in Canada. I wanted to share my experience because I wanted to give you an idea of my prospective. Clinical trials are conducted in a number of different settings. There are some differences such as in terminology but overall there is a common concept that we're going to be covering today. Through this lesson, I'm going to show you some examples of study materials mainly from our coordinating center to give you a better picture of what these study documents are like. A lot of the examples that I will be showing you are from Alzheimer's disease trials. But that said I'm very excited to talk to you about study documents. Just to start, I'm going to talk about what things you'll be able to do after we finish this lesson. You'll be able to identify study documents used in a clinical trial, you'll be able to explain why study documents are used, and you will be able to discuss principles and managing these documents. First, we're going to start with an overview. There are many types of study documents used in clinical trials. These documents serve many purposes. Study documents are used during all study stages, at the very start of the trial, even before it starts, while the trial is going, and also after the trial ends. What are the purposes of study documents in clinical trials? First of all, it guides study activities and coordinates activities in multiple places. In multi-center clinical trials, there's so many moving parts. There's a lot of coordination that occurs with a number of stakeholders. Study documents help pull this operation together and enables everyone to work together efficiently. Study documents provide a clear concise and consistent source of information for all participating parties. This is important because you don't want to have a lot of information floating around or documents. It's good to have one main official source of a study document. It also guides the data collection process. One of the most important things in a clinical trial are data. Data are very important because it's the meat of what you're doing. You need data to tell you if something works, that a treatment works if it's safe. Study documents help define how to collect data and as is the mechanism for collection. It also can describe how the study is monitored and audited. It guides the data collection process. Your documents help meet regulatory requirements. You need to be in compliance with all regulations, global, federal, institutional, and local agencies or you'll be shut down. You'll need to submit or show evidence of documents if you are asked. It also ensures good clinical practice. You want to do right by the patient, by the public, and you want to do what is best for his or her health. It also provides a historical record of activities. There is activities you might need to look at later which is important for when you go back and analyze data like reports, address audits, and even when you need to design future trials. Stakeholders. Multi-center trials are huge and it takes a lot of effort from a number of people. These are the stakeholders that are participating in a trial. It's good to understand all of these parties and how they use study documents to make the trial work. I'm first going to talk about investigators. Investigator is a person or people who are trying to see if an investigational product is safe and effective. Typically in an academic setting, we see that person is the one that gets awarded the grant. An industry, the company is typically the holder of the investigational new drug application. The investigator is trying to answer questions. Next, we have the funder. The funder is the person that provides money for the research efforts. It could be a government like NIH, it could be non-profit organizations or even private groups. Sponsor. You might look at the word sponsor here and think that I might have made a mistake, but sponsors have extra duties that funders don't necessarily have, like reporting serious adverse events. Funders could also be the sponsor, but the funder could choose not to have this responsibility and assign sponsor responsibilities over to another party. Coordinating centers or clinical research organizations. These organizations can take over sponsor duties. They coordinate research activities and manage the details of the trial coordination. They are like the heart of the operation pumping life and to the trial. In academia usually, it is a data coordinating center and usually in private or industry trials it's usually the CRO. Next, we have recruiting clinical sites. These are the sites that see the patients. They're on ground zero, they do the work. They are tasked with the clinical care of the patients and perform research duties. Institutional review or ethics boards, these are boards that ensure the safety and welfare of human subjects and are done in compliance with local rules and regulations. Well, NIH sponsor trials, we are now starting to move toward a requirement to have something called a single IRB. That means that there's one board that oversees a number of participating clinical site IRBs in their activities. These institutions might be from an academic setting, but there are also some boards that are private company that are unrelated to any institutions in the trial. Resource centers. There are a number of different types of research centers that might be used in a clinical trial. For example there might be labs and reading centers. It depends exactly what things you are studying and what you need. But for example you might be using a lab because you might be banking specimens or analyzing them. Also, medical monitors. These are the individuals that watch over the safety of the participants in the study. They are the people that need to be on call at all times. They have to be available to answer questions about eligibility or maybe address medical concerns of the patients participating in the study. Then there is something called the Data Safety Monitoring Board. They are a board of independent people who monitor the safety and efficacy of an intervention. They want to go and evaluate the risks that the patients are being exposed and that the benefit of the treatment is worth it. People on this board need to be free of conflict of interests. There are other monitors that participate in clinical trials too. Like people from a data coordinating center, or the CRO, the FDA, even local IRBs might monitor trials. Also, there's regulatory agencies like the Food and Drug Administration. They do a big part in guiding clinical trials. Finally, the public. Yes, that's us. Not only do we participate in the study research, we are also consumers of the research. We see the results, we benefit from the treatments, and even we're taxed dollars for some publicly sponsored trials, paid for these studies. Now that I talked about all the parties who need study documents, where do they live? You've got to have somewhere central to store all this important stuff. Documents should be stored in a central location at each location. Storage may be electronic or paper, but as time moves on we are moving towards electronic system. A trial master file and you might have heard it called TMF, should be stored at the sponsor or a coordinating center. There are also regulatory binders and it doesn't necessarily have to be a physical binder, it could be electronic binder for essential documents at local sites. Resource centers like pharmacies, labs also need documentation for them to keep in hand and also submit to the sponsor. Files and binders should be created early in the trial and maintained after closure. Records should be maintained so they can be pulled and audited at any time. The FDA, IRB and other regulatory agencies may need to access these. These are examples of some trial master file schema. These are ones that we have used in our centers over time. As you can see the paper-based to the far right, these are ones that we used very early at least in my career about 15 years, 18 years ago, they were paper-based. As you can see we took a little bit of time setting them up and trying to do all these things, thoughts about structure of those internal documents. But as time moves on we have moved towards an electronic filing system which it makes it very convenient and accessible to people, especially with this new working in home environment that has evolved after the onset of COVID. When you take a look at on the left electronic files, we have different folders here and within these different folders, there're subfolders and we know they have different components to them. What we try to do with this filing system is to keep the latest document at the top of the folder and then use a method of having a previous draft folder within. We do this in our center. I do like this method because sometimes when you open up a file and there's a gazillion files, it's hard to see which one is the most current. It's good to move older ones out of the way. We also have a name convention that our group uses and this is what I will talk about later in this talk. Here you see this is a regulatory binder checklists. As we mentioned this is something that clinical sites will have to maintain. This is a resource from NIH. They actually have a ton of great tools on their websites that could be a big help not only just this. But this is a list of the items that clinics should have in this binder and it's most likely that local IRBs will have a very similar list. They might actually have a little bit more detail or what, but it's something that it's good to keep in hand while you're organizing this binder if you should be working in a clinic, that's doing research. Next, I'm going to be talking about document creation. In fact, it all probably sounds pretty simple, but when you implement it many mistakes can happen. There can be multiple documents floating around and they're multiple people that could be editing them. If you don't have a system set up at the very start of this, it could create a whole bunch of extra work. Prevent yourself and others from a whole lot of wasted work and headache by thinking this through before you start. First of all, I just want to emphasize clear consistent terminology. Consistency among the documents are very important. Being clear is very important. Think about your audience, choose texts that is clear across regions. If you're working in different countries and things, make certain that you have a term that is familiar to all parties, and spell out stuff. Be very descriptive and clear. Define acronyms. As you might have realized the clinical trials have a ton of different acronyms and it does take a lot of time to learn them all. Do your reader a favor and spell them out. What we have also done that's a great help is to have a glossary in front of your document to define them for a quick access. Use consistent terminology. I know that many of us perhaps in high school we were all taught a beautiful thing about writing is to use different types of words in a paragraph so it doesn't sound repetitive. But here in clinical trials I strongly urge that it's very important to use the same term over and over again because that will minimize the amount of confusion. I know this probably sounds boring or very simple but it could be very confusing when you refer to something several different ways. For example, the questionnaire, and then you might use it something called an assessment or a handout. That is very confusing. If you just use the one-term questionnaire it can really help cut out a lot of ambiguity. Also, my final thing about the writing piece is be specific. For example, if it's a golden retriever use that term instead of a dog. It really will help the reader understand what you're talking about. Also, use a system to prevent multiple people editing at once. When you are writing this and you're using a team because when you are working with all those stakeholders and people, there's going to be a lot of cooks in the kitchen. Have a lead person coordinate the editing and writing effort. Have a system to manage your edits and to incorporate them. Send them out to the individuals for review and have a system of how to incorporate them in the right way. I strongly recommend using track changes, it's a great tool. If you forget to use track changes, there is something called Document Compare. It's great because you can compare previous versions and it will highlight all the changes between the documents. Also, I strongly recommend setting up a file naming convention for these different types of versions so you don't get confused. Also like I said previously, using a previous folder to put old drafts so you know which one is current when you go into the file. Next thing I wanted to talk about is version control. It's very important. Have a good version control numbering system. There might be different ways that you do this and it just depends on what you think would work best for your organization. But what we do for example, we use version numbers that also have decimals. For example, if we are working in a protocol that's a draft, we have it B0.0. As it gets to the point where we are going to submit it, and it goes into be an active protocol, we increase it to at 1.0. When there is a little minor change amendments to our protocol we will increase the digit in the tens place. It'd be like 1.1. But if there's a significant change, we end up increasing the whole number to a two or a three or something like that. That helps you understand at what protocol and what things that have occurred to it. I also recommend adding a version date to your documents too. Sometimes when you couple everything into changes for your study, the protocol which I'm going to be discussing later is the main document and sometimes when you change other documents that are related to the protocol, I would strongly recommend that having a version number on your protocol be that number but other documents that are related to the protocol to use a version date. Sometimes you've had clinics go back and get confused that if there is a document that is related to the protocol but the number is a little higher, it gets really confusing and people don't know what to do there. When you go in through, when you're editing documents, creating them, just think through all these different issues and how you would like to have them numbered. It will definitely like I said save your work and confusion and a lot of confused phone calls from your clinics. Clear documentation of changes between versions, that is very important for providing an audit trail like I said previously you might get audited from the FDA or different people so you want to be certain that you know what has happened between documents. What we do at our center which I find is very helpful, our documents are very major significant documents. In the front of it, we provide something called the document history. This document history lists the changes between each official versions and also the rationale why it was changed. It is really helpful to provide the snapshot because often our clinics have to submit it to their IRB or to get staff up to speed and to understand what the changes are between documents. Next, I'm going to be talking about access. When you get all your study documents designed and together, you need a way for everyone who's participating to access. This is an example of what we use in our center as a study website where all the study documents are available to our stakeholders is password protected. As you can see there are a number of different documents that we have here, but then you can click them and there'll be PDF versions out there. Also, one thing about clinical trials and you're working with a number of people, communication is always very important. When there are study document changes, we need to make certain that people are aware of them. We don't want them having to always be logging on to the website trying to take a look at something changed. What we do is we actually send out communications to our study team to let them know, hey one of these study documents something major has changed, and this is very important. This is an example of our internal system. It's something called our special study memos. We end up sending out them and they are numbered special memos. They represent something that's so important what we call as the force of the study protocol or special changes. We number each of these called PPMs, policies and procedure memoranda, and we label it with a subject, for example, Certification Materials, Protocol Version 1.2. Then we also have a release date. This, to your left, that list is on our study website, and when you click one of those buttons it will pop up with his communication, and you can see that we have it directed to certain of our participating stakeholders or parties. We'll go through and very clearly write exactly what this is about. Some trial information is available for the public in public view. Clinicaltrials.gov it is a resource that is available for all people to access. What you can do is you can learn about the clinical trials that are happening or going on and conducted and you can go and access this information onto their website. It will talk about the details of the study, what is being studied, like what condition, it'll talk about the eligibility, who can participate, what outcomes we are looking for, and what recruiting sites that are available. Eventually, over time when information comes in and the study is ending, you'll also be able to see the results. It's a great resource, especially if you want to participate in a clinical trial or you have an individual that suffering from something and maybe you want to see if there is some research that's out there. It's a great resource to use. Also PubMed. It's a publication database where you can actually go through and pull research articles that we'll discuss the results of these clinical trials and also we'll talk about study method. It's a very good tool to take a look through and you can google a lot of different things and you'll learn a lot about different clinical trials that had been conducted.
