Reporting to the IRB can mean navigating a maze of regulatory requirements. Staying current on what’s required – and what isn’t – is challenging. Join Quorum Review’s regulatory expert, Mitchell Parrish, JD, RAC, CIP, as he helps you concretely understand IRB reporting obligations.
In this webinar you’ll learn about:
The regulatory landscape driving IRB reporting
Problems with reporting to the IRB
Obligations for reporting safety information
Obligations for reporting non-safety information
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Quorum Review – Independent Review Board
You may also like the Unanticipated Problems Reporting Quick Reference.
MITCHELL PARRISH: Good morning to everyone. I’m definitely excited to be discussing this topic today: That is understanding reporting obligations to the IRB.
How I have organized this presentation the following way: First, I’m going to talk very briefly about the role of the IRB; why does the IRB even have to receive certain information. Also, what are some problems that currently exist with reporting information to the IRB. Then I’m going to cover very briefly the regulatory landscape out there to help us really understand where reporting obligations really come from. And then I will jump into the main part of the presentation. So that is, first, we are going to talk about the obligations for reporting safety information to the IRB then we will jump to the next main topic which is obligations for reporting what I call non‑safety information to the IRB. And, finally, I will wrap all of that up with key takeaways. So let’s get started.
First, the role of the IRB. Now, I think we all know really that the IRB’s role in the initial review of research and continuing review of research is to really protect the rights, safety, and welfare of research subjects. Now, how the IRBs are able do this, especially in the continual review context, is by receiving information from sponsors, the CROs, and the sites, information that really helps the IRB understand what additional steps it may have to take to protect those subjects in research.
So it seems simple enough, the IRB receives information from sites, sponsors, CROs, digests that information, and takes those additional steps. Well, if it were that easy, then it wouldn’t be one of the number one questions I get if I’m at a site or if I’m answering a question about what actually has to be reported to the IRB.
And here is just a very simple diagram to illustrate why it is such an easy concept. Well, not exactly. As we can all see here there is a lot going on. So if you look in that bottom right corner of this diagram, you have the PI. You have the site. They are conducting the research. There are adverse events that are happening. There could be anticipated problems that are occurring. And the PI is reporting these adverse events or these anticipated problems to the sponsor or the CRO, and the sponsor or CRO may be digesting this information and determining if its an anticipated problem or something of that nature that has to be reported to the IRB. Of course, it’s not always like that, the PI where the research is being conducted could also be reporting information to the IRB. Then, of course, there are all sorts of other reporting obligations, and this diagram doesn’t even begin to capture all of the reporting.
Then we have the IRB at the very top. So, of course, the IRB, once it receives information from the sponsor or CRO or site, it may have to take additional steps itself. For example, it may determine that something is an anticipated problem or there is serious continual noncompliance, and it itself may have to report to the institution, on the far left side, or the FDA on the other far side, or the Department of Health and Human Services. So there is a lot going on here. But what I really want to focus on what this presentation is about, is reporting obligations to the IRB. So it’s those gray lines that go directly to the IRB.
So let’s keep it focused today and really understand what those obligations are. Again, at the site you have the PI, that box on the bottom right side, you have the site they are conducting research, something happens, it’s an adverse event, there is some other problem that occurs. Of course, the PI can report directly to the IRB or the PI may be feeding that information to the sponsor who assesses that information and determines whether or not it has to be reported to the IRB. So really that’s where we are focused today are those two main gray arrows.
So with that, we saw a lot of arrows going everywhere, a lot of terminology. Of course there are problems with reporting and that’s why we are having this presentation today. Two of the main problems, the first one is unnecessary reporting. The IRB does end up getting a lot of information that does not have to actually be reported to it. And the problem with this is when the IRB gets inundated with all sorts of information that doesn’t actually meet any sort of reporting criteria, then there are thousands of documents the IRB has to sift through to really determine if there is anything the IRB has to take action on to protect the health, safety, and welfare of those human subjects. And, again, this isn’t just a problem that we see at Quorum and have noticed, it’s a problem that the FDA has definitely recognized, that’s why this quote up on your screen is actually this problem discussed by the FDA. So that’s the first problem is unnecessary reporting.
The next problem, along with the unnecessary reporting and all the information the IRB may receive, is that there also may be no explanation provided with the information that is reported. When there is no information provided to the IRB—so let’s say the IRB just receives a thousand adverse events—there is really no way for the IRB to assess. . .out of these thousand adverse events did the sponsor or did the sites think any of these actually qualify as an anticipated problem that has to actually be reported to the IRB. So it is tough, without any sort of background information, what’s being reported to the IRB. Again, this is a concern that was highlighted by the FDA. So there are two problems: There is unnecessary reporting and we also have reports where there is no explanation provided.
With that said, to address those two problems and to really understand today what to report to the IRB, let’s first look at the regulatory landscape and understand where the reporting obligations to the IRB actually come from and what actually has to be reported to the IRB.
So today this presentation is going to really focus on the Department of Health and Human Services regulation, I think we are all very familiar with that, also known as the common rule, that’s the 45 CFR 46. And then of course we have those FDA regulations, 21 CFR 56, governing IRBs; we have 21 CFR 312, talking about INDs, focusing on drugs there; we have 21 CFR 320, talking about bioavailability and bioequivalence requirements; and 21 CFR 812, investigational device exemption. So, again, of course, there are other regulations besides that, but really what I’m talking about today, it’s really focused on these regulations.
The other thing that this presentation focuses on that’s really helpful when thinking about what to report to the IRB are guidance documents produced by Health and Human Services and the Food and Drug Administration. So here I am going to be referencing a lot, a guidance document from basically AAHRPP, guidance on reviewing and reporting unanticipated problems involving risk to the subject or others. There is the FDA guidance for clinical investigators response sores and IRBs on reporting adverse events.
And finally, we have the newest guidance, which is for industry and investigator safety reporting requirements for IND, and BA and BE studies. So this is really where you can see I’ve taken my information on this presentation. And the reason I would like you to know exactly where this information is because it empowers you if you do ever have questions, you can go to these regulations or you can go to this guidance and really understand the reporting obligations.
So within those regulations and within that guidance is where the obligation to actually report information to the IRB resides. Report that safety information to the IRB? Well, I have the citations up there. It’s generally known that the IRB has to receive certain information, especially safety information, in order again to ensure the safety rights and welfare of the subjects. So we know the IRB has to receive certain information in order to do its job, but what information is that? That information is what we really call unanticipated problem information. So information that would be considered an unanticipated problem, whether that’s an adverse event or whether that’s something that’s not medically related, such as a problem at a site, for example, theft of a laptop that has participant data on it. So what we know from the regulations is that we have the term unanticipated problem, and this is actually the only information that has to be reported to the IRB in terms of what we are talking about for today’s presentation.
Again, because it’s actually not so clear, the term unanticipated problem, but let me point out where it exists in the regulations and sort of in the context it’s presented. So we know we have to report unanticipated problems to the IRB. Well, it’s found in 21 CFR 312, it says there the investigator shall promptly report to the IRB all unanticipated problems involving risk to human subjects or others. We also see this term in the context of the IRB in understanding that the IRB must have procedures for handling these unanticipated problems that are reported to the IRB. So again, this is really the focus there, that’s where we know IRBs have to receive unanticipated problem information.
While it’s nice that this term is in the regulations, what’s not so nice is that it’s not actually defined in the regulations, but we do get some help from guidance documents. So the most important guidance document in really understanding and defining what an unanticipated problem is comes from the Office of Human Research Protections or the Department of Health and Human Services research guidance, and from that guidance we know that an unanticipated problem that must be reported to IRB is any incident, experience, or outcome that meets all three of the following criteria: So only if it meets all three criteria must you report to the IRB.
The first criteria is it must be unexpected. This can be in terms of the events, for example, not being in the consent form or just not being in the investigator’s brochure, something that’s just really unexpected, and that can be that it wasn’t even on our radar this could happen, or it could be something we knew may happen in terms of risk, but it starts to happen more frequently than expected. So the first criteria is it must be unexpected.
The second criteria is the incident, experience, or outcome must be related or possibly related to a subject’s participation in the research.
And finally, the incident experience or outcome must suggest that the research places subjects or others at a greater risk of harm than was previously known or recognized. So it’s going to be key there. It’s not just a person was actually harmed, but that they could have been harmed.
So again, those three criteria are very important because it’s only that information that meets those three criteria, it’s only then that it is considered an unanticipated problem and must be reported to the IRB. So again, we have unanticipated, related or possibly related, and places subjects or others at a greater risk of harm.
In addition to defining unanticipated problem that guidance also tells us something else. That HHS guidance tells us that there may be those unanticipated problems out there that are related to adverse events, so related to basically medical occurrences. And there are those unanticipated problems that are not related to adverse events. So this is what I deem as those unanticipated problems that are not safety related.
So there we see how this presentation is organized today. We know that you must report unanticipated problems to the IRB, and you know that those unanticipated problems may be related to an adverse event, so therefore safety related, or are those anticipated problems that may not be related to an adverse event and therefore unanticipated problems that are non‑safety related. And I’m going to talk about both of these different things.
To highlight this concept that there are these unanticipated problems that can be related to adverse events or not related to adverse events, we have this diagram provided by the Department of Health and Human Services. So that far left side, that A piece that has been diagrammed, we have those adverse events that are not unanticipated problems. So we are not necessarily talking about these today. There is a lot of side effects that happen in research, but again if they don’t meet all criteria of unanticipated problem, they do not have to be reported to the IRB. What we are really focused on is that the piece, which are those adverse events that are actually unanticipated problems, so that would be a side effect that happens that wasn’t known previously, it wasn’t in the consent form, it wasn’t in the investigator’s brochure. And we also have that category C on that far right side. So here we have our unanticipated problems that are not related to safety information. Again, an example could be theft of a laptop at a site that has participant data. It would be an unanticipated problem but it’s not related to a medical occurrence.
So with that, let’s start off by talking about reporting to the investigator’s brochure that safety information. So that B part of the Venn diagram. This focuses on that left side of the Venn diagram, and like I already explained, in the middle, that part B are going to be the adverse events that do qualify as unanticipated and therefore must be reported to the IRB.
Let’s really dive into what that actually means, what safety information has to be reported to the IRB. So to do that, of course we have already gone over the term unanticipated problem. We know that something is unanticipated if it’s unexpected, related or possibly unrelated to the research, or places subjects or others at a greater risk of harm. We know that definition. That definition, however, is not too specific for our purposes.
So what I actually want to do to help us determine what safety information actually has to be reported to the IRB is I want to use two other terms, one term, I call SUSAR, serious and unexpected suspected adverse reactions, that’s for drugs. The other term is UADE, unanticipated adverse device effect. I’m going to use these two terms because what I want you to know is that if something is a UADE or if something is a SUSAR by its very nature by the criteria it meets there, it is an unanticipated problem that must be reported to the IRB. So know that we are still talking about reporting to the IRB in related to the unanticipated problem, but again we are going to focus on those two terms, but they help us really understand what safety information has to be actually be reported to the IRB.
So let’s look at that first term, SUSAR. A SUSAR, again, must be reported to the IRB because it inherently is an unanticipated problem. And the criteria for a SUSAR, is, one, serious. This seems simple enough, something is serious, and people have a general idea of what is serious. This could be death, an event that’s life threatening, in-patient hospitalization or prolongation of existing hospitalization. There is of course other things that could mean serious, too, listed there. I don’t need to list them all off. I think we have a general idea of what is actually serious.
The second criteria is unexpected. I also think this is pretty clear to understand. So an event that happens is unexpected if it’s, for example, a side effect that’s not listed in the investigator’s brochure, it’s not in a consent form or it’s not in the protocol. So really it is not expected that this event, this side effect should happen to participants. Again, we have serious, we have unexpected, I think those are quite clear.
Where it starts to get a bit more murky is in that third criteria, otherwise known as suspected adverse reaction. Here is where we really have to analyze what really is a suspected adverse reaction, and therefore what actually is a SUSAR that must be reported to the IRB. And a suspected adverse reaction is where there is a reasonable possibility that the drug caused the adverse event. In other words, there is actually evidence to suggest a causal relationship between the drug and the event. This is such an incredibly important point because it is this point that the FDA was really getting at in saying that the IRBs are being inundated with information that should actually not be reported to them. For example, they are receiving thousands of adverse events that aren’t really adverse events, it’s just related to disease progression in, for example, an elderly population.
So because I really think that’s the term that throws people off, I want to focus on what actually is a suspected adverse reaction. So, suspected adverse reaction, it’s where there is a reasonable possibility that the drug caused the adverse event. What the FDA has done to try to help us understand this term is it has also provided examples of what it considers a suspected adverse reaction.
The first class of examples of what it provides is what the FDA calls individual occurrences. The FDA explains these are a single occurrence of an event that is uncommon and known to be strongly associated with drug exposure. So some examples would be angioedema, hepatic injury, and Stevens‑Johnson syndrome.
So because if a participant experiences one of these injuries, you know that there is such a strong relation between this injury and drug exposure, you know there is likely a reasonable possibility that the drug actually caused the adverse event, therefore it is a suspected adverse reaction. And if it is unexpected and serious, of course, it must be reported to the IRB.
So let’s test our knowledge. Let’s make sure we really understand the concept of this individual occurrence. So I’m actually going to turn now out to all of you listening today and ask you a question and ask for your participation. So in my example I say, in a phase‑two study, testing for an investigational drug for Hepatitis C, a subject experiences hepatic injury. In addition to the investigational drug, the subject was continuing her standard Hepatitis C therapy at the time of the hepatic injury. Taking this into account, do we think this is an individual occurrence that is a suspected adverse reaction? I’m going to give the audience about 30 seconds to provide your feedback.
Okay. It looks like our answers are in. Thanks for everyone’s participation. It looks like 60 percent of you said yes, this is an individual occurrence that would be classified as a suspected adverse reaction. And about 40 percent of you said no. I like this breakdown, and the reason I like this breakdown is I really do think this can be debatable, and that was the intent of this question. But my answer is going to be yes in this instance and let me tell you why. Although the injury could have been caused by the subject’s standard therapy or through disease progression, hepatic injury is strongly associated with drug exposure. Since this is the case, even with these other confounding factors there is a reasonable possibility that the drug caused the adverse event. I know this is a little bit debatable, but that’s my rationale for saying why this individual occurrence could be unexpected adverse reaction.
Now, the next category that the FDA provides is the category called one or more occurrences. So what the FDA explains this means is one or more occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug. An example here would be tendon rupture.
So let’s test our knowledge about one or more occurrences and whether or not one or more occurrences would be considered a suspected adverse reaction. Again, I’m going to turn this out to the audience. My example is a subject with extra pulmonary small cell carcinoma receiving an investigational chemotherapy agent experiences a bowel perforation during his second cycle of chemotherapy. Is this one occurrence a suspected adverse reaction? Again, I will give you about 30 seconds to answer this question.
Okay. Looks like we have our poll closed and our answers are in. Here we have about 59 percent of the people saying yes, this is a suspected adverse reaction. And the other percentage is saying no, this is not a suspected adverse reaction.
My answer this time is going to be no. And again, let me explain, because the questions that I wrote are meant to introduce kind of that gray area. Again, this is the reason why one of the number one questions we get is what has to be reported to the IRB and why we are even discussing this topic today. So my rationale for my answer about why this one occurrence is not a suspected adverse reaction is the following: Bowel perforation is not commonly associated with drug exposure. That’s key. And bowel perforation is seen in cancer patients. Therefore, while there is some literature produced on chemo‑induced bowel perforation, this one event is not reportable. However, if there were more than just this one occurrence of bowel perforation then I would say reconsideration should be given as to whether to report the events as more than one occurrence. So the difference between this one and the last example, the last example there was that a strong association between the event that happened and drug exposure. This one not quite so much.
And the final category that the FDA provides to help us understand what is really a suspected adverse reaction is what the FDA calls aggregate analysis of specific events. This is an aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group. So this aggregate analysis is really, really important because in terms of the FDA’s guidance saying Department of Health and Human Services saying what actually has to be reported to the IRB, one of their number one things that they point out is that just one event is reported and that may not signal a reasonable possibility that the drug caused the adverse event. What the FDA really is trying to get everyone to do is do this aggregate analysis, look at various events in the totality to get a better sense of whether or not there is a reasonable possibility that the event that’s occurring is related to the study product.
So let’s test our knowledge about this category. My example is 17 oncology sites are participating in a research study comparing an investigational chemotherapy agent to standard therapy in subjects ages 60 to 85. Of those subjects receiving investigational drug an average of 35 percent of the subjects across the 17 sites experience deep vein thrombosis. Does this aggregate analysis indicate a suspected adverse reaction? I will give you about 30 seconds.
Okay. Looks like our polls are closed and our answers are in. We have 88 percent of the population saying yes and we have 12 percent saying no. Here I’m going to agree with the majority this time and I’m going to say yes, I do think, based on this aggregate analysis, that the deep vein thrombosis would be a suspected adverse reaction. And here’s my rationale for that. While deep vein thrombosis is common in cancer patients, 35 percent of the subjects receiving investigational drug experience deep vein thrombosis. While this may be related to each subject’s cancer an aggregate 35 percent could indicate there is a reasonable possibility that the investigational drug is causing the event. So that’s why I say yes to this example.
So, again, it’s really critical to understand the concept of suspected adverse reaction. It’s important to understand what the three criteria are, which are serious, unexpected, and suspected adverse reaction. So it’s important to know that. And it’s important also to feed into that definition those examples that the FDA provides; individual occurrences, one or more occurrences, and aggregate analysis. If you really understand suspected adverse reaction and understand serious unexpected, so that whole SUSAR term, this helps us avoid what the FDA explains are significant problems in terms of reporting, especially reporting information to the IRB.
So some examples that the FDA says ‑‑ if you really don’t understand what a SUSAR is and if you don’t understand what a suspected adverse reaction ‑‑ there may be those serious adverse experiences reported that are unlikely to have been manifestations of the underlying disease, so mortality or major morbidity. You may always reported those serious adverse experiences that commonly occur in the study population independent of drug exposure. So there could be strokes or acute myocardial infarction in an elderly population. Again, may not meet the criteria of a SUSAR, serious unexpected, but a key piece suspected adverse reaction.
And, finally, the FDA says if you don’t really understand that term you may end up reporting serious adverse experiences that were study end points. So as an example, the study was evaluating whether the drug produced the rate of these events. If you don’t understand this term and really don’t understand that difficult piece of suspected adverse reaction.
Again, the IRB has all sorts of information that’s really just a drain on resources in terms of the people reporting to the IRB and in terms of the IRB receiving this information which really isn’t beneficial because these things don’t mean they are a SUSAR, in other words, an unanticipated problem the IRB should be taking action on. So that was the term SUSAR, again, if something is inherently a SUSAR, it is an unanticipated problem that must be reported to the IRB. So SUSAR is a term associated with drugs.
Now I’m going to talk about a term associated with devices. So that term is UADE, or unanticipated adverse device effect. If something is a UADE, by its very nature it is an unanticipated problem that must be reported to the IRB.
So what are actually the criteria for a UADE? The first criteria, serious. Just like with SUSAR, first criteria is serious. Again, this could be death, life threatening, or a serious problem. I think we have a general grasp about what serious means.
The second criteria is not previously identified. So also similar to SUSAR, in terms of the unexpected criteria. So not previously identified could be an effect not previously identified in its nature, severity, or degree of incidence in the investigational plan. So in the device manual or in the protocol or somewhere else.
And the final criteria of a UADE is caused by or associated with a device. Here, this really links up with the term for SUSAR, suspected adverse reaction. So really it’s written differently, it’s tailored toward devices, but generally it’s the same criteria we see in a SUSAR, it’s for a UADE. And it’s not just me saying this, the FDA also, if you look at its guidance that it produced for clinical investigator sponsors of IRBs in terms of adverse event reporting of IRBs it even comes out and says you should be reporting UADEs to the IRB, just like you should be reporting SUSARs to the IRB. So essentially UADEs and SUSARs should be treated the same. Again, we know they have slightly different terminology, but they should be handled the same in terms of really analyzing is it serious, is it unexpected, and is it related to the device. Only if all three criteria are met should be you reporting this to the IRB.
The other thing to take into account, since the FDA did equate a UADE to a SUSAR in that guidance, is think about those examples that the FDA provided. So, again, that example of individual occurrence in a device trial or one or more occurrences in a device trial or if there are multiple occurrences determined through an aggregate analysis. So those are still beneficial categories for us to really think through whether or not an event that happens in a trial is actually related to the device.
Now, in terms of recommended practices for reporting safety information, so we know that you have to report to the IRB unanticipated problems, and we know for drug studies and device studies we have those specific terms, SUSAR and UADE that by their very nature are unanticipated problems and must be reported to the IRB.
So what’s the best way to actually report to the IRB? The FDA provides some real nice guidance here in terms of how to report. And what it suggests for multi‑center studies is that while the investigator really understands the causality piece, the investigator is right there, they are the one assessing the patient and the actual adverse event that occurred. Again, it’s going to be so important in a multi‑center trial to really analyze more than just one occurrence, to do that aggregate analysis of data and adverse events from multiple sites to determine if there is a reasonable possibility that the drug or device actually caused the event.
What the FDA suggests for multi‑center trials is there can be an arrangement through the sites and the CRO sponsor in terms of who actually reports that safety information to the IRB, who actually reports those unanticipated problems to the IRB. So because the FDA recommends this, of course, we as the IRB think this is a good idea. This doesn’t always have to be the case. Investigators can always report directly to the IRB. But generally, like the FDA says, the sponsor is in a better position to process and analyze the significance of AE information for multiple sites. And you can go ahead and have this arrangement where the site submits to the sponsor, and the sponsor is the one that determines what to submit to the IRB as long as this arrangement is made explicit between the various components. So the sponsor of the site and the IRB, when that arrangement is in place, then you understand who is going to report that information to the IRB.
If you need help developing this arrangement, you can always work with the IRB. The IRB is there as a resource and can help you understand and navigate what actually should be reported to it, and who is going to be doing it—what contact from the CRO, what contact from the sponsor, or if it will be the site. So again, don’t forget to use the IRB as a resource. That’s one tip.
The other thing I want to point out is—because after going through this presentation so far we know there are only certain things that have to be reported to the IRB—those are unanticipated problems that, you know, could be a SUSAR or a UADE, but know this: If the protocol states blanketly that all adverse events have to be reported to the IRB, this is very problematic because then we can’t engage and only report what is necessary because you have to follow the protocol. So this is sort of a warning: In the protocol be sure there is not a general statement about reporting all adverse events. Because if there is, then of course, everyone is going to be obligated to report all information, which is going to do away with our whole point of analyzing what actually has to be reported to the IRB. So make sure in the protocol it doesn’t have that blanket statement.
Now, that was for multi‑center trials. Of course if there is a single center trial or investigator‑initiated study, of course it’s the investigator that’s likely going to be the one reporting to the IRB. This still means that the investigator can talk to the IRB and arrange what actual format to report to the IRB. And I still have my same tips here. In the protocol it should not state that all adverse events are going to be reported to the IRB. Again, it’s only those adverse events that are SUSAR or UADE, and therefore by their very nature are an unanticipated problem that must be reported to the IRB. So I caution you there on the protocol.
Now, what about timing? So we know that the sponsor can report or the site can report, but what the FDA has recommended for those multi‑center trials is really the sponsor or CRO should be analyzing, determining what to report to the IRB.
In terms of when to report, we have to report to the IRB promptly. That is the term used. Promptly. Well, promptly is only really defined in guidance documents. And promptly, from the FDA’s vantage is generally considered 10 business days, which generally is reported by the FDA guidance. So 10 business days. And this is 10 business days from when the investigator may learn of the event. Again, this may become tricky in aggregate analysis. Because in an aggregate analysis, you really don’t know that something may be reportable to the IRB until after all the events are analyzed. So, again, you have to understand there that 10 business days may be applied to determining something is an adverse event after conducting that aggregate analysis.
And the other thing to caution you here is this 10‑day time frame exists whether or not the investigator is going to report to the IRB or whether or not the sponsor will report to the IRB. That 10‑day time frame exists generally from when the event is discovered. Again, with the caveat about the whole aggregate analysis piece.
Finally, if there are any questions about what to report in terms of safety reporting to the IRB ‑‑ so, again, unanticipated problems ‑‑ that could be the SUSAR or that UADE, talk to the IRB. The IRB is the one you are reporting to, the IRB should be able to inform you what to report, whether to report, how to report, and when to report.
Okay. We are done talking about reporting of that safety information to the IRB. Now I want to switch gears and talk about obligations to reporting non‑safety information to the IRB. So now going back to that Venn diagram we have seen twice, I’m in that far column, that C column, unanticipated problems that are not adverse events.
So here we are talking about unanticipated problems that are not actually related to a medical occurrence. So we are not talking about that typical injury from a side effect or something like that. Here we are talking about what’s usually a problem at a site. So, again, I have used this example before, but the theft of a laptop that has participant information on it. This could be an unanticipated problem that has to be reported to the IRB but it’s not necessarily an adverse event.
So let’s figure out what to report for non‑safety information to the IRB. Here we have that same term that we had for safety information, we have an unanticipated problem. But this time we are not going to get into the SUSAR or the UADE, we are just sticking with the term unanticipated problem. And, again, to reiterate the three criteria of an unanticipated problem, it is unexpected, related, or possibly related to the research and places subject or others at a greater risk of harm than was previously known or recognized. If all three criteria are met, you must report to the IRB.
Let’s look at some examples of unanticipated problems. An example could be a failure to obtain informed consent. At Quorum, we require that major protocol deviations are reported to the IRB. So this could be if there is a violation of the inclusion or exclusion criteria, or if a study procedure was omitted, things of that nature could rise to the level of an unanticipated problem. There could be study personnel misconduct that adversely impacts the study. There could be adverse findings by a regulatory agency, medical board, or other relevant body.
So, for example, let’s say you have a PI at a site. You find out that the PI’s medical license has been suspended for harming one of their patients or something of that nature. Well, the IRB should know about this because this could very well be an unanticipated problem; it’s unexpected, it could be serious. And by the nature of the participant being with that investigator they could be placed at a greater risk of harm than was previously known or recognized.
The key thing to remember in terms of figuring out what actually is an unanticipated problem that must be reported to the IRB, you really have to understand the circumstances and the specific factors surrounding the unanticipated problem. So again, it’s not always cut and dry about what is an unanticipated problem, but understand those three criteria. That will really help guide you on what actually should be reported to the IRB.
Now, to help us understand the term “unanticipated problem” in the context of reporting this non‑safety information to the IRB. Let’s go through a few examples. The first example, I’m going to turn this out to the audience, is an investigator is conducting behavior research and collects individually identifiable sensitive information about illicit drug use by surveying college students. The data is stored on a laptop computer that is password protected. The laptop is stolen from the investigator’s car. My question to all of you is: Is this reportable to the IRB as an unanticipated problem? I will give you about 30 seconds to answer that question.
Okay, we have closed the polls. The answers are in. We have a resounding 91 percent of you answering yes and 9 percent answering no. I’m going to agree with the majority here and say, yes, this is an unanticipated problem.
So a laptop stolen has identifiable data. If this gets into the wrong hands this could definitely place subjects at a greater risk or harm than was previously known or recognized. It is related to the participation of research and it’s certainly unexpected that a laptop would be stolen. Now, the laptop is password protected, but again, it could be very easy to overcome this. For example, on some laptops, you can just remove the hard drive, place it back in the laptop, and that does away with the password protection. So there is still the chance that a participant could be placed at a greater risk of harm. So I would say yes, this is an unanticipated problem that must be reported to the IRB.
Our next example, the investigator is conducting a psychology study evaluating decision‑making and response times when persons are listening to music at various decibel levels. In order to perform the study, participants are placed in a small, windowless sound‑proof booth. The IRB approved protocol and consent form describe claustrophobic reactions as one of the research risks. One of the twelve subjects enrolled in the research experiences a significant claustrophobia resulting in the subject withdrawing from the study. Is this reportable to the IRB as an unanticipated problem? 30 seconds.
Okay. The polls are closed, the answers are in. We have 88 percent answering no, this is not an unanticipated problem. And we have 12 percent answering yes, this is an unanticipated problem. I’m going to say no, this is not an unanticipated problem. Experiencing claustrophobia could be serious, being in the study may have placed this participant at a greater risk of harm: This person probably would not have experienced claustrophobia but for being in this study. But the key here is it’s not unexpected. So claustrophobia was actually listed as a risk in the research. So because it was listed, it was expected and therefore it does not meet one of those critical criteria for actually calling something an unanticipated problem. So no, I would not say this is an unanticipated problem.
And our final example today, as a result of a processing error by a pharmacy technician, a subject enrolled in a multi‑center clinical trial receives a dose of an experimental agency that is 10 times higher than the dose dictated by IRB protocol. While the dosing error increases the risk of manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after a careful period of observation. Is this reportable to the IRB as an unanticipated problem? I will give you 30 seconds for this final question.
Okay. We have 93 percent of you answering yes, this is an unanticipated problem and 7 percent answering no, this is not. My answer is yes, this is an unanticipated problem. Again, the three criteria, unexpected, this is definitely unexpected. You wouldn’t expect that the dose was given at 10 times higher. Is it serious? Yes, it is serious in terms of what could happen and that’s really the key. Because while the person wasn’t actually harmed, it placed the subject at a greater risk of harm than was previously known or recognized. So that’s sort of the key part that I think the 7 percent of you might have got mixed up on, is that while the person wasn’t actually harmed, they very well could have, and that is sort of the key. So we have our unexpected, we know it’s related to the research, and the subject was placed at a greater risk of harm. So my answer is yes there.
Okay. Now in terms of recommended practices for reporting unanticipated problems to the IRB, again, for multi‑center or single center, I’m going to combine these two here because when we are talking about reporting unanticipated problems that are not safety related, we are not talking about the SUSAR, we are not talking about the UADE, we are talking about non‑safety related information. Generally these occurrences happen at a site. So because it happens at a site we typically expect the site is going to be the one reporting the unanticipated problem to the IRB as opposed to the site providing information to the sponsor or CRO who is then going to provide it to the IRB. Not to say that arrangement can’t happen, it’s that it’s going to be most common. We probably recommend that the site just report directly to the IRB. Again, the investigator can arrange in terms of what format to report to the IRB. For example, Quorum Review IRB has an unanticipated problem form in which to report certain occurrences to Quorum.
Timing for unanticipated problems, reporting to the IRB, here again, the term “promptly.” And promptly, looking at the FDA’s guidance, it’s generally considered 10 business days from when the event is discovered. So here, we would certainly hope at a site if there is an unanticipated problem, again—theft of a laptop, informed consent was missed and someone was enrolled that didn’t meet the inclusion/exclusion criteria and that placed them at a greater risk of harm—we would expect that to be reported within 10 business days. And again, the arrangement for unanticipated problems is typically going to come from the site. But if there isn’t an arrangement with the sponsor or CRO, understand that the 10 business day time frame exists and starts when the event is discovered. So no matter the arrangement, it is a 10 business day time frame.
If there are any questions whatsoever about reporting unanticipated problems to the IRB, again, report contact IRB. They are the one that should have the policies and procedures about what should be reported to them. So if you have questions about what to report, whether to report, how to report, when to report, contact the IRB. They are there as a resource.
Now let’s wrap up with the key takeaways from today. First, know where the obligations to report to the IRB originate. I gave you those regulations and the guidance documents at first, but really understand that you know what to report to the IRB because of that term unanticipated problem, and that term unanticipated problem has three criteria—unexpected, related, places the subjects at greater risk of harm than was previously known or recognized. So know that’s really what makes up you are obligated to the report to the IRB.
In terms of drugs or devices, understand the term SUSAR and UADE and know their criteria. Because if you know their criteria, inherently these are unanticipated problems that require reporting to the IRB.
Finally, understand that there are unanticipated problems that are not safety related. So those that are not related to a medical occurrence, but these also may be reported to the IRB if they meet all three criteria of unanticipated problem. And in terms of reporting these unanticipated problems related to safety information or non‑safety information, know the time frame and know how to report to your IRB.
The IRB is there as a resource, so contact them and use them. Quorum is here. Quorum Review IRB is available to help with reporting. There are regulatory staff available to help with site and sponsor/CRO information to answer any questions you have about reporting to Quorum. With that I appreciate your time very much.