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Medical receipt format for Research and Development

>>Anne Zajicek: Hello. I'm Dr. Anne Zajicek. I am a pediatrician and PharmD. >> Lisa Cordes: Hi. I'm Lisa Cordes. I'm an oncology clinical pharmacy specialist and educator. >> Anne Zajicek: And we will be discussing using the protocol template, and I've included two links for the protocol template. As a short background on the template, the staff at the National Institutes of Health and the Office of Science Policy and staff from the review divisions of the U.S. Food and Drug Administration held a series of meetings to develop a mutually agreeable protocol template. The reasons for this was a lack of clarity on the part of the NIH-funded investigators about what was needed in a clinical protocol as part of an investigational new drug application, otherwise known as the IND, or an investigational device exemption, IDE, application, and the FDA wanted to be clear about what they needed in reviewing these applications. As an added benefit, this template auto-populates some of the clinicaltrials.gov fields, making it easier to submit your protocol to that website or protocol registration and reporting. I'm going to show a series of screenshots of the tool, and then Dr. Cordes and I will do a live demonstration of the tool. So, let's take a look. On the website for the introduction to the principles and practice of clinical research, there is a button for protocol templates. If you click on that, it will provide three types of protocol templates. There is the e-Protocol writing tool, which I'll be discussing today. There's also an example of one for the National Center for Complementary and Integrative Health and one from the NIH StrokeNet. This is a link to the NIH grants and funding website, which notes the existence of the clinical e-Protocol writing tool and three benefits, which include enabling participation for multiple writers and reviewers, allows assignments for reviewers and collaborators, and tracks the progress and ensures document version control. And again, we'll be demonstrating this in a live demo. If you page down, there are also Word templates if you do not want to use the e-Protocol writing tool. There are two types of Word templates, one for phase two and three clinical trials that require FDA, IND, or IDE applications, and there's also a template for behavioral and social sciences research involving humans. And again, those are two separate templates. Of note, the purpose of the templates was to provide a format for phase two and three clinical trials, but that's not to say that the formatting can't be used for phase one trials, for example, or even phase four clinical trials. And some of the fields that are in the template may be irrelevant to the trial that you are doing. So going back to this webpage about grants and funding and the clinical e-Protocol writing tool, I am going to click on the button, and this will take us to the e-Protocol writing tool and the sign-in. And I'm going to be discussing at some length about the help button at the top. Moving down the page, the e-Protocol writing tool is useful for collaboration and writing, to track the progress, and to export the protocol, including to clinicaltrials.gov. This is the link to the e-Protocol writing tool. And next, I'd like to talk about the help button on the upper right. So, clicking the button on the upper righthand corner will give a series of helpful screens explain how to use the e-Protocol writing tool. So, if you click on the e-Protocol writing tool link, you will get to this screen. If you click on the protocol button, you'll get to the first screen, which asks you to create a new protocol. Both templates are on this website. So, there's the phase two, three clinical trial template, and then there's the behavioral and social sciences research involving human template, and you'll choose one of those. You will choose a protocol name and then a protocol short name, and you'll click the create protocol button. And this will bring you to the protocol editor, which is the main point of this lecture. So, in the upper righthand corner, you'll see a variety of buttons, including the preview, export, clinicaltrials.gov, manage team, and finalize. The preview button allows you to view your protocol in a more concise format. The export button transforms the protocol to Microsoft Word with a draft watermark format. The clinicaltrials.gov button allows you to auto-populate clinicaltrials.gov registration and reporting, and manage team allows you to enter protocol authors and the reviewers. Paging down to the bottom of the page, there's a question for you to select study type, and there are three options, observational, interventional, and expanded access. And just to explain those, observational is to do a study looking at, generally speaking, the natural history of a disease. Interventional is a study where you are doing intervention to change that natural history of the disease. And expanded access, your third choice, is another word for compassionate use, where an investigational drug is used for a patient who is not part of a larger clinical trial. These are screenshots of preview. Again, this gives you a more concise format to view what you've typed in. Export -- again, this is watermarked with the word draft on it, and this allows you to send it, for example, via email to you and your co-investigators. Manage team allows you to add authors and the section that they are writing, reviewers and the section they would be reviewing, and then you can save the changes in the lower righthand corner. This is the protocol editor, and I wanted to point out one extremely useful button here. So, as you click down and look at these various sections, for example, the protocol summary, if you have a question about what the synopsis is, what the schema is, what the scheduled activities, and so on are, there's a really nice screen that opens up explaining what those activities involve. And I wanted to point out one that I thought was extremely helpful, and that had to do with schedule of activities. And it notes that allowable windows should be stated for all visits, and I can't tell you how useful this advice is. For example, if you're expecting a patient to come on day 30 of the protocol and the patient comes on day 28, if you're very clear that the patient needed to show up on day 30, you will have to submit a protocol deviation. This gets very complicated during a trial when you haven't allowed any noise around the time for the visit or, you know, times for pharmacokinetic sampling, so I just wanted to point this out. Anyway, this is very helpful. And now I will shift to the live demonstration of the e-Protocol tool, and Dr. Cordes and I will go through the tool. So, I signed into the protocol writing tool, and now I'm in the protocol writing tool, and I will start now. So, first thing I want to do is to create a new protocol. You have an option here, again, of phase two, phase three clinical trial, or behavioral and social sciences. I'm going to choose the first one, the phase two, three clinical trial. The protocol name is going to be -- let's just pick something simple -- protocol demo. And the short name -- the protocol names tend to be fairly long, is to pick something short, so I'm going to go with demo. And I click create protocol. Okay. So here are the table of contents, which I'm going to go through in a second. This is the study type. Then we discussed that previously. Then there's a choice of observational, interventional, and expanded access, so let's go with interventional. What is the name of the funding agency? So if you were not being funded by one of the NIH institutes -- and it's likely you were not -- just click other. And then they will ask you the name of the group or person funding your trial and the name of the IND or IDE sponsor. Save changes. Then I want to start talking about the table of contents. So, the first of all is the title page, this page. Protocol amendment summary of changes table -- and this is extremely helpful, because at some point there probably will be changes in your protocol, and you want to make sure you're keeping track of them. The first reason is you want to know what the changes are and why you changed them, and the second point is that when you have a different version, like version two, but you have patients that signed the consent form for version one, you may need to re-consent them depending on what the institutional review board decides. So, this is important. And the other point is that if you get audited, if the FDA comes to audit your trial, they will want to make sure that your patients have consented to the protocol version that they are being treated under. So, it's very helpful. The statement of compliance, this just states that you are doing the study ing to the clinical practice. And as we go through this, you'll see that there are different pop-ups here. So, protocol summary is going to include the synopsis, and again, these instructions are extremely helpful to explain what the synopsis is, what is being asked of you, the schema. Instructions here are also very nice. This is a diagram. What's going to happen during your trial? Schedule of activities -- again, with instructions, and again, a very helpful point about the windows. Go through the introduction, and the introduction will consist of the study rationale, the background, and the risk benefit assessment. And by the time that people get through reading your background, they should be very clear on why you're doing this protocol and the fact that benefit will outweigh the risk. Section three contains objectives and endpoints, including study design, the overall design, scientific rationale for the study design, justification for the dose, why you picked this dose, and justification for the route of administration. Just as a point here, if you're going to give a drug whose dosage form doesn't exist before the start of the trial, you should probably stop. Section 4.3, justification for the dose -- provide a justification for the route of administration and the dose, the dosage regimen. And section 4.4 -- end of study definition. Section five -- the study population with inclusion criteria, exclusion criteria, lifestyle considerations, including food and drink restrictions, smoking, alcohol, what to do with people who you thought were going to be able to be enrolled but aren't, and strategies for recruitment and retention. This tends to be a problem with trials that people you recruit end up dropping out of the study, so you need to make every effort to retain the patients that you've enrolled in the project. The study intervention -- study interventions, again, administration, preparation, handling, storage, and accountability. This is where you really want a pharm assistant volunteer to make sure that the medication is available and that it's being accounted for. Manages to minimize bias -- another way to put that would be randomization and blinding. How will you be doing that? Who will be doing that? Study intervention compliance -- so, how do you know that the patients you enrolled in the study are actually complying with the protocol? Are they taking the medication? Are they not taking the medication? How do you verify that? And then concomitant therapy -- what else are the patients taking? Are they taking standard of care on top of the medication that you're using in the trial, for example? It's important that if you, at some point, are going to want to collect what patients are taking at the same time of your study drug, it's helpful to have decided that up front and collected that information. It is very difficult to get it after the fact. And now I will turn the system over to Dr. Cordes. >> Lisa Cordes: Thank you, Dr. Zajicek. So, starting with section seven of the protocol, this is focused on the discontinuation of study intervention and participants coming off a study. This section should clearly state which adverse events require discontinuation of the intervention. And it's also important to note here that participants can withdraw from the study at any time that they wish to, so that needs to be documented in this section as well. Section 7.3 describes the nature and duration of the follow-up, and occasionally patients or participants cannot be reached for follow-up, and this section needs to discuss how to handle that situation and describe plans to minimize missing data for that. Section eight provides details related to study assessments. This section should list and describe all the study procedures and evaluations that are done to support efficacy endpoints of the study. These can be timelines and procedures for administering the study intervention, for example. And it's important to remember that the protocol should contain a high-level discussion of the process, but further detail can be provided in the manual of procedures. And section eight is very similar to section -- I'm sorry. Section 8.1 is very similar to section 8.1, only it's focused more on safety assessment. So, examples here would be, you know, when are you going to be conducting your physical exams and laboratory evaluations. Section 8.3 is focused on adverse events and serious adverse events, and it's broken down into multiple different sub-sections. The instructions here do a great job of providing some definitions for you and help you guide, you know, the wording that you're going to be using in this section. And then section 8.4 outlines unanticipated problems. It's important to include these details because a situation that meets the definition of an unanticipated problem generally requires the principal investigator to consider changing the protocol or changing the consent. And the responsibilities of reporting the unanticipated problem should also be outlined in this section. There's a whole section of statistical considerations. Our course provides a lot of valuable lectures on this topic or writing details of the section of the protocol, so I highly encourage you to view those. Briefly, this section will include the physical hypotheses, sample size determination, the study population, and also the planned statistical method. Section 10 here provides details on supporting documentation and operational considerations. The first section here is focused on regulatory, ethical, and study oversight. The procedures for obtaining and documenting informed consent, for example, are going to be included here. And always remember special considerations for consent, such as children who are being consented or other individuals or vulnerable populations that cannot consent on their own behalf. Confidentiality and privacy details should also be outlined here. Examples of other considerations for this section are quality assurance, data handling, and also record keeping. One other very important tool of this protocol writing tool is that we have a abbreviations section here, so this has a lot of the common abbreviations we use in clinical trials. And there also is an abbreviations section that's included in our IPPCR protocol webpage as well, in the portal, so make sure you check that out, because that can be helpful if this page is missing any of the common abbreviations that you might say. Section 10.4 will include the protocol amendment history. As Dr. Zajicek mentioned before, it's very important to make sure this is tracked carefully. You should document the version, the date, the description of the change, and also just a brief rationale as to why those changes were [inaudible]. Another helpful feature of this tool is the ability to easily incorporate references. References should be incorporated throughout the protocol as you use them, and I'll show you example of that process. For example, if you are writing a background section of the introduction potion here, you can simply click the place in your document that you would like to include a reference. Then you can click add reference, and then that will bring you to a search box. Let's say I'm going to be adding one of Dr. Zajicek's references. I'm just going to type in her name here and hit search. And let's say I'm going to pick this first reference here at the top. All you have to do is select import reference. It's going to then out a subscript here, a number right where you are typing, and this will keep track of all your references in order, kind of like EndNote does, if you're familiar with that processing system. So, once you have that added, just make sure you hit save. And then when you go to the references button here at the bottom, there you're going to see a reference automatically added to the site. So, it's a very useful tool to be able to add your references easily. That concludes our overview of the e-Protocol writing tool. I will turn it over to Dr. Zajicek to share our final comments. >> Anne Zajicek: So, for our final comments regarding the e-Protocol writing tool, point number one, be accurate and clear. The FDA will review this protocol for safety and determine if it can go ahead -- in other words, recruitment can begin -- or place it on clinical hold. The manual of operations and the manual of procedures are based on this protocol. If the protocol is not clear, these documents will not be correct. The template does provide version control, and again, this is an issue with informed consent versions. You want to make sure that the patient has signed the version of the informed consent from the version of the treatment protocol that they are on. This protocol template populates the clinicaltrials.gov template for mandatory clinical trials registration and reporting, which is very helpful. As I mentioned before, not all of the template protocol elements may be relevant to your protocol. The template was designed for phase two, three clinical studies. You may be doing a phase one or a phase four protocol, so some of the elements that are in this template may not be relevant to you, and that's okay. Please apply for a clinicaltrials.gov number and an IND or IDE as soon as possible. The information that you submit to the clinicaltrials.gov website is reviewed by the NIH National Library of Medicine staff. There may be some alterations. There may be some questions that they have for you. So please apply for it early and assume that it will take a few days at least. And Dr. Cordes and I wish you good luck with your clinical trial.