So we’re going to continue staying on the topic of IRBs and we’re going to slowly segway ourselves into Regulatory Documents. This is something that you at the research clinic will probably have to do at some point, or at least you should be familiar with. So let’s start with the forms that the IRB would need. As previously mentioned, the IRB must grant the approval for the study sponsor to conduct the clinical trial, and the sponsor’s may have 30 sites across the country that they’ve selected. So now each one of those sites has to get approved by an IRB. Sometimes those sites needs to be approved by a local IRB, which means an IRB that they’ve probably been working with before. This is often the case at academic institutions but most of the time private clinics at least can use central IRBs. These are the IRBs that the sponsor works with to kind of make a streamlined approach to getting all the sites approved and up and running.
6.1 IRB submission report
So what an IRB needs is the IRB submission report from each site. And what this is, this usually a 12- to 15-page document which lists who the principal investigator is going to be, who his or her support staff is, how many years of experience do they have, who the coordinators are, how many years of experience do they have, the recruitment methods that will most likely be used for the study, how will the subjects be recruited. Are you going to be recruiting from the economically disadvantaged population and therefore run the risk of maybe coercing them into joining the studies due to paying them money? Are you going to be recruiting any other vulnerable populations, let’s say, illiterate people who can’t read, people who can’t speak the language, things like that. The IRB looks at these things. They also look at GCP. They want to know when was the last time the principal investigator and his staff have had GCP training. And by the way, GCP training should be done once a year at least, at a minimum. Also, have you taken a course on protecting human subjects? The NIH has a very good tool, a free resource for providing training on protecting human subjects.
So these are the things that the IRB looks at and the study coordinator is typically the one responsible for completing the IRB submission form. However, the PI has to review it, and sign it, and approve it before it gets submitted to the IRB. In addition to this, the IRB would most likely want to see a copy of the Informed Consent form. Not only do they want to make sure that all the risks and potential benefits of the study are explained in an easy to understand manner for the study participants, but they want to make sure that the study participant understands what he or she is getting himself into and how much they can be compensated for the study, how much they can be compensated for their parking, their travel, their time, things like that. They also want to make sure that there are phone numbers there for the PI to be able to answer any questions or any emergency phone calls from the study participants. And they also want to make sure that the study sponsor is listed and the reason and purpose of the clinical trial.
Again, to avoid coercion, to avoid therapeutic misconception, and to basically ensure as much as the IRB can that the study participant who joins a clinical trial fully understands what he or she is getting into and that it’s clearly explained in the informed consent. This is another thing that the IRB will look at when you’re submitting your site for study start-up.
6.2 Regulatory documents
So now let’s move on the Regulatory Documents and these are everyone’s favorite. But basically, once a research site has agreed on to take a study, the site initiation or regulatory process will begin and what this means is, continuous communication with IRB, continuous communication with the study sponsor, filing adverse events that we’ve talked about, filing SAEs. Similar to the IRB submission forms, we have the Continuing or Review forms sent to the IRB every 6 months and those are reviewed by the IRB as an ongoing basis once the site is up and running. They want to make sure that the site is still adhering to Good Clinical Practice and that unnecessary harm and unnecessary risks are being avoided at the site. These are things that also are considered regulatory documents although still related to the IRB. But now let’s talk about the actual regulatory documents because these are things that the IRB will need to see before they approve the research site and give them the green light to go ahead and start conducting the trial and enrolling study participants. So once IRB approval is obtained, the site will receive the approved documents and this must be filed in the Regulatory binder, also called Study File Notebook and kept separate from the clinical source papers of where the actual study data is being recorded for the study participants. So usually the coordinator is in charge of keeping track of these forms although the principal investigator is ultimately responsible for the timely upkeep of these forms.
6.3 The 1572 Form
The most important form in clinical trials by far, at least from a regulatory standpoint is the 1572 form. The PI listed on the study must complete a 1571 form that the sponsor will file with the FDA. The coordinator will fill out the information and the PI will generally sign and date the form. The 1572 form provides the FDA with:
- Investigator’s name
- Address and
- Curriculum vitae (Resume)
The form must include the name of all sub-investigators. A sub-investigator is generally a medical professional, it could be an MD, but doesn’t have to be, it could be a nurse, it could be a nurse practitioner, and it could be a physician assistant. Basically anyone who’s clinically involved in the study.
Now there’s some demand as to whether as to why there are study coordinators actually, sub-investigator. I’ve seen studies where they are listed as sub-investigators. I’ve seen others where they’re not. It depends on exactly what role the coordinator is doing and we’ll talk about that more when we get to the delegation of duties log section later in this chapter. But for now just know the names of all people who will be assisting in the research, as well as each location where the trial will be carried out for your site. So let’s say your site has 2 clinics or 3 clinics, you must list the addresses of all of them where the study will be taking place. In short, while the 1572 it is the most important form from a regulatory standpoint, it’s very simple. Its 1 page, front and back document which has this information as well as the protocol title on there. And it’s a contract in which the PI basically promises the FDA that he or she will conduct the trial in accordance with Good Clinical Practice. There we go again – GCP as you can see. It’s pretty important to follow GCP and so that’s what the 1572 is. Once the investigator signs it, he or she agrees that he’s going to make sure that the trials run with all Good Clinical Practice practices in accordance with them.
6.4 The Clinical Trial Study Protocol
Now you have the actual protocol. So this is important because you obviously want to make sure you’re following this. Remember we talked about protocol deviations. So you don’t want those. You don’t want protocol deviations. You want to make sure that the PI, the sub-I’s the coordinators are all familiar with the protocol and back and this must be kept in the study binder as well, and the originals must be signed and dated by the principal investigator. Any amendments to the protocol which the sponsor routinely makes amendments as they see fit. The amendments may be small things, it may be big things, but the amendments must be understood and of course have to be approved by the IRB before they are put into place. But once the amendments are there, it oftentimes requires the study participants to sign the IC again. Even the ones who are already in the study, if there were any changes made that would impact them.
Another thing to put in the study file notebook or the regulatory binder is updated versions of the curriculum vitae or the CV of investigators and study staff, copies of the PI and sub-PI’s licenses. Medical licenses must be kept on file. The CV’s and licenses obviously should be up to date. They should be signed and dated. Now if they are not up to date, you will get an audit and the monitor (CRA) will make sure that you get them updated.
You also want the IRB Approval Letter so when you are given the approval to begin screening you want to have that on file and this document must be kept in a binder as this is proof that the site has received IRB approval.
Copy of lab certificates and reference values – these are important for the people who are actually going to be processing the blood samples etc. Oftentimes the CROs who we’ve talked with have their own central labs where you from your research clinic will ship the blood to them. They will then process them. You still need to have their certificates there in place.
Copy of drug brochure – So the investigator brochure talks about and it’s oftentimes 200-300 pages. It lets the researchers know exactly what is known about the study drug to date so it talks about things to look out for, what they have experienced in previous studies. This is important because the PI or the researchers, if they know about this information, they could be looking out for it when their study participants are being seen by them on a weekly basis, monthly basis, whatever it may be. So this can be referred to when a patient asks about a particular side effect and generally these will be in the Informed Consent as well.
And then you need the original signed and stamped IRB-approved consent form. So this is the Informed Consent form that the IRB has approved and has stamped and each time there’s a protocol amendment they will have to issue another consent form and stamped again. So only the Informed
Consents that have been stamped, sealed and dated by the IRB can be used to consent patients. A coordinator should never use a template of the Informed Consent that has not been stamped by the IRB as ‘approved’. So you obviously want to have the right form with you. You want to make sure that it has a stamp on the bottom of every page by your IRB that is dated, and you want to make sure that you’re always using the latest version. I’ve seen people get in trouble when they’re not using the latest version.
Another thing in the Regulatory binder is advertisement approvals and letters, again from the IRB. We’ve talked about this. All protocol amendments, all IRB updates and notifications including SAEs from other sites around the world, so you want your PI to make sure that he or she understands what other research clinics are reporting as far as their SAEs.
And you want financial disclosure forms. So anyone who is involved with the study, PI, sub-PI, not always coordinators but it depends on the sponsor, anyone who has access to data and could potentially skew the data to create a favored outcome must sign a Financial Disclosure form and what this form states, is that it makes the statement whether the PI or the sub-PI’s or any of the researchers have a financial interest in the research company that’s sponsoring the trial. So if a biotech company is sponsoring a trial and you have a PI who’s doing the trial who’s maybe an investor in that biotech company, there’s obviously could be a conflict of interest there and if the PI is an investor he can still do the study but he’s got to let the FDA know that he is an investor so they’ll obviously be looking at him or her more closely. But it gives an extra layer of transparency and just shows that there may be not any financial conflict of interest there.
And finally, all study-related correspondents – So anytime CRO or a monitor sends you a letter, it must be documented in a file chronologically in the study binder. Same thing with any continuing IRB reports. Same thing when you’re closing a study, kind of the opposite of when you’re starting a study. You need to submit a Final Closeout form to the IRB and then they will see whether you ran the study with Good Clinical Practice, if there are any outstanding issues that must be resolved before they can finally close out the site and give you the close out letter, and all drug receipts, records and inventories, and we’re going to talk more about investigation of product in future chapters.
6.5 Enrollment and screening log
Now we’re going to move on to when patients, or study participants, are actually coming to the clinic and we’re going to start with Enrollment and Screening Log and that’s just what it sounds like. It’s a log that you’ve got to keep and send to the sponsor either by fax or email on a weekly basis just so they know how many new study participants you’re planning to screen and how many you have screened. We’re going to get into the details later such as the different types of visits like e.g. Screening Visit and Randomization Visit.
6.6 Informed consent
For now, I wanna talk to you about Informed Consent, because I promised to you a chapter by itself. I’m going to try and keep this one relatively short. I mean, an Informed Consent is basically like I said earlier, has to be approved by the IRB, has to list what the study is, what the purpose of the study is, what the potential benefits and the risks are, and also lists emergency numbers, how much the person’s going to get compensated for participating in the trial, how long the study is, what type of procedure’s they’re going to be, are there going to be ECG’s? Are there going to be blood draws? Are there going to be diaries? Are there going to be computer tests? We’ll talk about this in later chapters. But basically that’s what Informed Consent is and it’s roughly 15 pages, sometimes 20 pages.
They have different versions of consent forms that have to be resigned whenever there’s a protocol amendment. Then you have your various State forms like I mentioned the California Bill of Rights earlier. So this go together with the consent form. And then you have sub-consents like genetic consent form. Some studies also have a portion of the study where they’ll do genetic testing. They’ll do a genome type on the person if they choose to. Oftentimes the way these studies are structured is that these genetic portions of the test are optional but there is a separate consent form for that and I won’t waste your time with that. But basically, the consent form is, you want the PI or someone involved with the study to sit down in a private room with the study participant. The study participant should be encouraged to bring family or friends who can help them make this decision if they want or they can do it on their own. It’s up to the study participant.
Now if it’s a minor, they need to have a parent or legal guardian in the room with them to sign the consent form. And the minor, they need to give assent because they’re not old enough to give consent but they need to give assent which means they understand the general nature of what’s going on. But that’s the exception. Let’s get to the actual informed consent.
You want to be in a private room. You want to have preferably the PI there present to answer any medical questions. You really go through the document and take as much time as the study participant needs. You really want to make sure he or she is comfortable with this and that he or she really understands what the purpose is. You don’t want them to come back to you later and say, ‘I did not understand that this was part of the study.’ You should have all the stuff laid out in front of them and take as much time as you need. Roughly, the whole process of Informed Consent takes 30 to 40 minutes depending on how long the paperwork is. For the doctor, the physician or someone knowledgeable with the study to explain to the participant everything they want to know to answer all their questions. The study participant does not necessarily have to sign the form that day. They can take it home. They can review it with their loved ones, their family, and their friends and then they can come back with it and sign it and go through the consent form again.
But you cannot start the screening process. You cannot start the study until that form is signed and it’s got to be signed on that day that they do the study or they can sign it at the day before they do it as long as it’s not signed after you started because that would be a protocol deviation and that would not be adhering to good clinical practice. You cannot do anything related to the study before getting the informed consent signed. And then you must have a process of informed consent where usually the principal investigator or the study coordinator will write a quick note describing the process of the Informed Consent, whether the study participant had any questions, whether these were addressed, and things like that. Who was there with the patient? Did they have any concerns? You want to make sure that this process, this is documented so that if you were to get audited that you have a paper trail showing Good Clinical Practice.
Here I should throw in that the Informed Consent – it’s a process. It’s not just a one-time event. Any time the patient’s in a study is an opportunity to do another informed consent. That doesn’t necessarily mean going through the documents again ‘coz you already did that once. Unless there’s a new consent form that the IRB is thinking that they would need to sign but what I mean by Informed Consent is just, constantly keeping the communication flow open between you and the study participant to let them know that, ‘Hey, this is what we’re looking at. How’s everything going? You know that you can withdraw at any time if you want. If you’re not comfortable with any other procedures you can refuse them.’ You got to make sure this is understood and of course document it or else it did not happen. In research, if you don’t document, it did not happen. But that’s basically what you need to know about the Informed Consent and I don’t think I should throw it in is once they signed the Informed Consent and the PI has signed the Informed Consent or another researcher has signed it, you can give them a copy. You actually should give them a copy to take home with them so that they could have that information there with them and those emergency numbers there with them.
6.7 Delegation of duties log
And at this point, I should probably talk about Delegation of Duties as it’s in the Regulatory binder. We covered this in the previous chapter but just again, the Delegation of Duties log will spell out every single person involved with that study. The PI, the sub-PI’s, the study coordinators, the research assistants, the people drawing the blood, every single person will be listed on there. It’s different in the 1572 however, because it’s more detaile It shows who’s involved, what they’ll be doing and of course there’s a section there that says who is doing informed consent and it could be a number of people. Whoever the PI thinks is appropriate to do the informed consent can do it but they’ve got to be on the Delegation of Duties log and they should be kept in the Regulatory binder.
So hopes this help, this section on Informed Consent. I mean you just make sure you’re following Good Clinical Practice and essentially when they’re filling out the form they must initial the bottom of every page and dated. One of my pet-peeves is that often people have sloppy initials and I understand. I am the same way but in research, you really have to make sure that, you have to emphasize that they clearly write their initials and clearly write the date and that they be consistent with their date. And if they mess up on the consent form, if they put the wrong date for example, they need to do what you do as a researcher – take a pen, cross it out with a single line, and write the correct, i. They should do this as well because it is a legal document and it is something that could potentially be audited so you should follow Good Clinical Practice there too. Hope this helps.