Diving into Single IRB Implementation

Author: Jenni Beadles, Assistant Director for sIRB Operations at Mass General Brigham IRB and Lauren Hartsmith, Director of Regulatory Affairs at Advarra

About the Advarra In Conversations With…

The future of healthcare innovation hinges on research and clinical trials. Advarra sits down with leading experts to dig into pressing issues and explore cornerstone solutions. Join us as we discuss topics and trends impacting the healthcare of tomorrow and advancing clinical research to be safer, smarter, faster.

 

About This Episode

How does single IRB (sIRB) actually work in practice? In this episode, we get an inside look at how institutions implement sIRB requirements and how to overcome potential challenges with relying on an outside IRB.

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Hi, everybody, and welcome back to the Advarra in Conversations with… Podcast. My name is Lauren Hartsmith, and I’m the director of regulatory affairs of Advarra. I’m excited today to be joined by Jenni Beadles to discuss the interesting topic of single IRB implementation and it really is a fascinating deep dive into IRB operations.

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Thank you so much, Lauren. I’m excited to be here. My name is Jenni Beadles, as Lauren mentioned, and I am the Assistant Director for single IRB operations at the Mass General Brigham IRB, where my primary responsibilities are really supporting our multiple institutions through single IRB operations, and also IRB reliance management.

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Awesome. Well, thank you again for joining us today and I’m really excited to be having this conversation with you. So, without further ado, let’s get started. So before I ask you my first few questions, I just want to lay a little foundation of what single IRB means, and why we’re talking about it today. So historically right, the IRB system has been very decentralized. So you know, some sort of ethics review has been required for a very long time in this country, but kind of the modern idea of the Institutional Review Board that really is an outgrowth of regulatory work done in the seventies and finalized throughout the eighties. And the idea at that time was that each institution doing research. And when we say institutions we’re talking about, you know, organizations that might be receiving Federal funding

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or pharmaceutical companies that for whatever reason they’re developing projects, and they might be under the FDA regulations, they might be also under the HHS regulations administered by the office for human research protections or OHRP. So the idea is that you know one IRB one institution.

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That was just how the regs were written, and how the system was originally set up. And again, in the seventies and eighties That made sense. But of course, as technology has advanced, we really saw in the nineties and early 2000s, this explosion of multi-site research and the one IRB one institution model didn’t quite work as well when you had multiple institutions trying to engage in the the exact same research activity, but you had different IRBs trying to implement, these regulations. And so, just from an administrative perspective it was really complicated in terms of how do you get these studies off the ground? And let’s say you have a hundred sites, and each site is trying to review these protocols.

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So one of the ideas coming out of the Fed, NIH did some did some um administrative tests, and they tried a couple of different models of you know. How can we, How can we do this process in a way for these multi-site studies? How can we engage in this process in a way that doesn’t compromise Ethics review at all, but is more efficient in terms of study startup time and study and in development of,

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of, or engaging in, these clinical trials. And so the idea that NIH had been working with and what they finalized in a policy, I believe around 2016, and it was implemented in two thousand and eighteen is this idea of mandating single IRB Review. The idea is that there’s one IRB of record where, if there’s any compliance issues right, that’s who the Fed would go to talk about compliance issues, and they are the IRB that’s in charge.

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And then other IRBs would have a supporting role in the reviews of these studies, and that supporting role would be defined by the IRB of Record and the other IRBs, just in terms of which responsibilities each would have again, with the understanding that the IRB of record is the one who at the end of the day is responsible for all compliance type issues. This type of review structure was always permitted by the regulations.

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it wasn’t as heavily used as NIH data suggested. It could be in order to help minimize um help to promote efficiencies while not compromising ethics review.

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So you have the NIH developed a policy um when office of Human research protections again, That’s OHRP and it’s part of HHS, when they updated the common rule in 2017, 2018, When that update was finalized, there was a single IRB mandate included in the common rule regulations, and so that would apply to anything to any research that was uh, any multi-site research that was conducted or supported by a common rule department or agency.

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And Then, more recently, just this year In fact, FDA published a notice of proposed rulemaking so a draft rule, making to update their regulations to also require this single IRB mandate in certain in multi-site research that subject to FDA regulations. So they published their draft rule, making in September. The public comment period is still open, I believe. And so we’re hitting a point

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where this, where the topic of single IRB is, is really it’s one of the hot topics in the field, and there’s lots of questions about. Well, how do we implement this in the best way? How should we at an institutional office be thinking about it?  And so that’s a lot of what we’re going to talk about today? OHRP just issued. a draft single IRB guidance. And so we’re going to talk about that and the implications of that. But we’re also just going to talk about more broadly, and

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just think things that folks should be thinking about as they as they update policies and procedures in their offices, and think about right. How do we engage in this world where you know all of the major regulatory authorities are now requiring single IRB?

Chapter 2: Single IRB Implementation in Practice: Challenges & Efficiencies

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So, Jenni, you have so much on the ground experience, and so I’d love to get your perspective on how single IRB Review works in practice,

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Yes, I’m happy to do that. Thank you so much, Lauren, for that introduction to the topic. I do think that the guidance itself, and single IRB in general does offer a wonderful resource for study teams who are participating in multi-site clinical trials, I think we definitely have seen some gains there, but also some challenges. So some of the challenges of implementation, For example, have to do with institutional policies and procedures. And How do you ensure that those policies and procedures are being followed when your IRB is not at that particular institution. So what has been implemented and continues: Um,

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even now in practice, is what’s called a local context review. So those institutions are still doing some level of review. Now it’s not another IRB review, but it is another review that that many times requires a submission to the IRB office again, not for IRB review, but to review the overall submission and consent form to ensure that local policies and procedures have been met, and that any ancillary reviews that may need to be done, and ancillary reviews are things

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that don’t fall under the purview of the IRB Review that are things like Radiation Review, IBC Review, Pharmacy Review, so many of those um local reviews that need to be addressed are still having to come into an IRB office at each institution for some level of review. So I think that

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while there are a lot of efficiencies to single IRB in general, there’s just still a lot of learning to do on the part of research teams and IRB. Still, even though this has been going on for four years now at least, There’s still a lot to be learned, and a lot to streamline in that process.

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It sounds a little bit, though, like the efficiencies, and correct me if I’m miss speaking here, but it sounds almost like because of the local context reviews, and because, you know, there’s still an expectation for local group or local IRB to still be doing something. Um,

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You know that in terms of efficiencies Whether or not you see a lot of time saving in the beginning, I think it sounds almost like that study dependent. But once you get through that part of the process, then, you know amendments and continuing review, and that sort of thing. and that’s very straightforward, and you do see a lot of those time saving measures. Does that sound accurate?

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Yes, that’s actually a great point, because that is exactly what we are seeing, and I uh, I was previously at Vanderbilt’s IRB for many, many years, and also working on single IRB there. I just recently moved to Mass General Brigham this year to also work on single IRB here,

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and that is, that is the challenge, and I think is where some of the disconnect with the communication with study teams is because they’re expecting it to be so much quicker

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that they’re expecting that from the beginning and the onboarding process and the establishing of IRB reliance between the reviewing IRB and all of the relying institutions can be very time consuming. And so, it really does help to have kind of an established reliance process that you follow at your institution. So I think we want to avoid allowing multiple IRB reviews of the same protocol, because then I think there it just causes a lot of confusion among study teams, and just from a regulatory perspective like who has the regulatory

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authority. And so I will mention here that that actually is one of the points in the OHRP Guidance is whether or not an institution involved in cooperative research can conduct or could choose to conduct It’s own IRB Review, and OHRP Has allowed for this in their guidance. They say yes, and I do think that that’s one of the points that I would respectfully disagree on, because I think that that does create some confusion about the single IRB mandate in general. Well, the additional IRB reviews can happen so. Yes, that they that they’re telling. And it’s institutions that yes, you can choose to do your own internal IRB Review. Um. But and they do say in the guidance that that those reviews would not have any regulatory status with regard to compliance, but just the fact that they’re allowed to happen. I think that that could just further delay the onboarding process for sites

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Right. Because then you have. You have the IRB of record saying, Here is our findings. Here’s the changes that we think might be required, Let’s say, in a protocol or in an ICF, And then you have this other review that exists that you still need to figure out what to do with.

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But you know, and from a regulatory perspective, you can do these reviews. But then, how do you manage the fact that there might be differing opinion? You know reasonable minds can absolutely differ in this field, as we well know, but right, what do you do when the IRB record is saying one thing, and there might be some requested changes from another IRB as their administrative review.

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Yes, yes, great point. And then on top of that, you have funders and study teams reaching out to you. If you are the reviewing IRB, asking you, how long is this going to take? Is this is taking too long? and we always tell study teams.

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You’re only as fast as your relying institutions. So if the relying institution is taking a long time to agree to the reliance or complete all of their reliance documentation in order for you to serve as the reviewing IRB. That’s just adding on to the time

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Can you talk a little bit about the reliance process? you know, I think from what I saw when I was working for OHRP Is that, you know, for example, right?

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a site that has a very robust research program, They’re able to manage the reliance process pretty efficiently, but you know you might end up with a site that you want to use for a whole host of reasons, but they might not be a site that just in that has a that has a very large research program. And so, for them, getting through the reliance process can be a little trickier. And just for those who don’t know, there’s documentation requirements when you’re an institution who is relying on a single IRB of record, and you’re not relying on your own IRB for a review. And so We talk about reliance agreements, but it’s the documentation that’s necessary to outline,

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And who’s responsible for what? Who is serving as the IRB of record, and noting that the other IRB is ceding review to the IRB of record. So, Jenni, can you talk a little bit more about the reliance process, and where things can slow down in that process?

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Yes, definitely. And this also is one of the items in the guidance from OHRP about the documentation requirements, and so, I think that it is critical for institutions who are willing to serve as a single IRB to identify early on what is your process and follow it Like you, you need to have an established process. So, for example, uh, we have decided at Mass General Brigham, that our preferred

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IRB reliance agreement is the smart IRB authorization agreement. When we’re serving as the single IRB of record, everyone who’s coming to rely on us has to either sign on to that agreement if they haven’t already, or if they have, then it we document that we’re using the smart IRB agreement.

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Then what you need to know after that is that some sites aren’t able to sign on to smart IRB for whatever reason

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if they’re unable to, You need to have some type of agreement at your site that you’re willing to use for sites that are not able to sign on to your preferred agreement.

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Uh. So that’s something that we have. And when I’m talking about signing on to agreements, these are IRB reliance agreements that have to be executed between the IRB and the institutions who want to rely on your IRB Review.

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When we’re using the smart IRB agreement, we have very established workflow there, so we have a flexibilities document with the uh, like a letter of acknowledgment uh That’s more study specific to say, Okay, we’re using the smart IRB agreement for this specific study. Just so it’s documented how the reliance has been entered into, and so um

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that’s one of the things we use, and for those times that we aren’t able to use smart IRB, we have our own institutional

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IRB Reliance agreement. Granted, it’s closely modeled after the smart IRB agreement itself. Because what you’re looking for in those agreements is kind of delineation of responsibilities, right? You want to know what the reviewing IRB responsible for and what is the relying institution responsible for so just making sure that you have an established process, I think it’s critical to identify that early on.

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And then how you’re going to collect documentation from the sites. it really helps when you have some system support within your institution. It’s something that I know We’re working on at Mass General Brigham.

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But that is a very, That’s a great point, Lauren, and it is something that’s critical for institutions to have developed before entering into agreeing to be a single IRB.

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Right. Can you talk a little bit more about smart IRB? from my understanding, it’s a model of how the single IRB process can work that was developed independently of these different mandates, so it’s kind of a consortium approach, almost. And there’s you know, there’s a model agreement, and basically institutions can say, yes, I agree with this. And anybody who has any other institution who’s agreed to this particular framework. This is the model that we’re going to use, and we don’t need to negotiate our own reliance agreement, and that right. And the idea is that that in and of itself can save time, and they also have lots of other resources

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I’d love to hear a little bit more from your perspective about smart IRB and how that model can be helpful.

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Yes, I’m glad to do that. I think that smart IRB has taken us to a different level with single IRB reliance agreements. Reliance agreements have come a long way than the early iterations of reliance, agreements that that were available, either through OHRP or from somewhere else where it may have been just one or two pages.

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To now several pages where we’re outlining the um responsibilities of each side, and it’s really clear which is very helpful when single IRB is mandated, because, you know, when it’s mandated, you really do need some clear roles and responsibilities for each of the sites.

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But the smart IRB agreement is a master single sign on agreement. So sites are all signing the same exact agreement. It’s a non-negotiable agreement. So, everyone signing the same the same terms. Uh, once you have signed on and joined, you are listed as what they call a participating institution on their website, and those participating institutions are public facing, so everybody can see who has signed on to the agreement. And so you would already have a very, very wide

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population of institutions that you could potentially enter into a reliance agreement with, because they have well over a thousand institutions nationwide that have signed on.

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as part of being a single IRB, you’re charged with collecting local considerations from your relying institutions,

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and so they do provide resources for how to collect that information, whether it’s a survey, or a questionnaire, or however, you prefer to do that, or you can take their resources and make them your own like how you would like to document either the flexibilities of the agreement

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um, and also some of the flexible terms within the agreement. Uh for the roles and responsibilities of the of the institutions.

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So one of the other things that that we’ve talked a lot about so far  in this conversation is difference between, like a local context or local considerations review versus a full IRB review and this was something that the OHRP guidance also hits on So I’d love to hear a little bit more from you about from your perspective, What are the types of things that are most appropriate to be in a local consideration?

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That’s really the question of the year. I think that this varies from institution to institution, and I also think that it would be helpful to have more guidance from on what those really need to be. Some of the guidance that they do provide refer to things like um, local circumstances or preferences, or any variability like cultural and language um differences, geography, and things like that. So you do have to take into account, that’s why it’s so important to have the documentation of the local considerations from the site itself, because, as the reviewing IRB, you’re not there, you’re not immersed in it. So, you have to ask those questions to get at: What are your local community attitudes toward research, for example? Uh, tell us more about what’s required, and at your institution do you have a policy about this particular you know about enrolling, I don’t know prisoners. If the study involves vulnerable populations, what are your local policies about that, and tell us what you’re able to do there, because it really becomes

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a challenge for the reviewing IRB, when you know how to review for your own site about a lot of a lot of those issues. But you don’t know other State laws. You don’t know what their laws are. You’re, you’re relying on them to provide you with that information so that you can make an informed decision about adding them as a site, and what they need to do, or if anything should be different for that site.

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Right. That’s yeah, I often say to people right, our regulations are very squishy that that we’re working with. And so there really are I mean just so many different ways that you can implement certain provisions, and you’re absolutely right, You know just the extent to which research involving prisoners lead the process that type of research will go through right There’s specific regs for sure on what happens if that research is HHS funded. But the operational approach of your institution, and can differ so widely in order to comply with that with those regs.

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I can see I can see points like that, being, you know, not a sticking point per se. But there’s a lot of different permutations. You have to think about when entering into the Reliance agreement? Um! To make sure that when these situations come up, everyone’s on the same page about how to manage them.

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Another question that I had for you is, on that point, you know it also sounds like in these reliance agreements, the single IRB of record has an opportunity to be very strict about what types of input they’ll consider from the relying institution. How does that impact the single IRB process from your perspective?

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Would you say that taking a more permissive approach is helpful, being stricter about which sections you know about what areas that the relying institutions can have more um more. Say You know I don’t know if there’s one approach that you found. That seems to work a little bit better, or if it’s a case-by-case scenario?

Chapter 3: Implementation Strategies and Considerations

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I do think it’s important to approach it you know, of course, from a mutually respectful position. I mean, you want to respect, you know what the relying institution needs, but also have a set and established policy in place that allows you to serve as the single IRB without being all over the place, so you know, be able to keep that organized in an a more efficient way. And I do think that would increase efficiency for sure, but one of the ways that we implemented this, when I was at Vanderbilt, was the use of a two part consent form. This is something that

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multiple other institutions have started to use, and when I say a two-part consent form, it’s not two different forms. It’s just one consent form with two very distinct sections, and what we found is that you can move all of the information into the first section that is about the protocol that would apply to any site participating in the study. So that’s your risks and benefits, and you know all of the procedures and things that are going on.

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So, all the study specific information gets moved into that part one. And then your second section really addresses what each site, the variability that you know, So the required the required sections of the consent form.

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Some of those are local, so they’re implemented locally, so like HIPAA, language or subject injury, language, or things that would tend to vary from site to site. Those would be moved into the second section of the consent form. That’s also where the local investigator and local contact information would be documented in that second section,

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what we found is it was it was challenging to implement it, because people didn’t understand it at first. what ended up happening is that everyone loved it. Our committees loved it because it was clear what was coming from the local sites that were relying on you. The study teams loved it because they all they had to do was send that second section of the consent to the relying institution for them to complete, based on their local considerations that they needed to provide. So that was one way to manage

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all of that local and local context information, at least through one of the study documents which is the most important in as far as I’m concerned, from a human subject Protection Perspective is the consent form. And so to be able to have a consent form where you say, Okay, none of this in section one is up for grabs like You can’t edit anything in this section. One where you can edit is everything in Section two. And then those two sections are used together to for legally effective, informed consent form. So that’s one of the ways that we were able to do that.

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My final question for you today, What are the IRB of Records responsibilities Vis a vi the applicable state and local laws, and then also so it addresses, what are the requirements of the single IRB to know and understand?  The local laws of the different sites that they’re doing reviews for, and then also what might be some nice to have on the nice to have list, OHRP mentions that right maintaining some kind of documentation so that sites can access and apply relevant state and local law. I wish that they would provide some more concrete examples

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of what are types of you local um laws or regulations that might relate to a one eleven determination. Instead, they just note that there’s they give an example of the type of legal knowledge that the single IRB would not need to possess. Um. So I would love for additional clarification there. Um. But yeah, but from your perspective, too, I would. I would love to hear you know

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what you think about that approach from OHRP But also just if you have any suggestions in your experience of local laws, where it really where in your experience it is helpful for the single IRB to be knowledgeable of those or there’s other approaches that you’ve seen work in terms of the single IRB getting the information that they need in order to make the appropriate one eleven determinations.

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That’s a great question, there’s been multiple examples of when it’s helpful to know the sites local context, and one example in particular that’s standing out. Is that um!

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There was a site in another It was another state in another region of the country that had had some legal issues with regarding enrolling certain study populations. And so this particular study involved those populations, and so from our IRBs perspective., and this may have been at my previous institution, but it was we reviewed and approved the study no issues. And so when the review went out to all of the sites, a particular site came back and said, “We can’t do this here. We need you to make a determination about this particular thing.” and so,

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from our IRBs perspective, we were like, Well, you know, this is single IRB. We met all of the regulatory requirements. And so what ended up happening was that that particular issue that their site had

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got moved into a local consideration issue they had to review and approve it locally as part of their local consideration or local context review, because it wasn’t regulatory. It didn’t have anything to do with the IRB Review, really, but it really had more to do with a State law or a local policy that they had. So

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you know, that could have gone a different way. That decision could have been a very different decision. But that’s what we That’s how we ended up addressing that particular issue is that we moved it into the category of local context. But I do think, going back to, you know, having a like a national database, or something where sites can go to reference State laws, or State preferences, or anything like that would be a great resource, and I think many IRBs would agree with that.

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Yeah, and it does seem like, at this point in time, this guidance it hasn’t been finalized yet, So it’s still in draft form which means you know it’s a helpful resource, but it’s not a finalization of OHRP’s current thinking on the topic. It’s. It’s just draft

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um, but it does sound like the way that these sorts of local legal considerations have been handled is by, you know, basically single IRB is do the best they can for some of the obvious things like age of majority. And if other issues come up that ends up as part of the local context review, and so it becomes something that the local sites can manage, since they are in a better position to know all of those details as opposed to the single IRB, especially if they’re not necessarily in the same geographic location. Um,

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I think that is yeah, I think that’s definitely an option. I you know I don’t know that it could be, You know I don’t know that I would broadly apply it just to say I would just move it to local context. But I think it would be it would. It would depend on what it is, and that particular instance it was not a regulatory determination. So if it doesn’t affect the regulatory determination that must be made by the IRB, and I think that it’s an option for sites to assume that as part of their local context review.

00;29;40;24 –> 00;30;17;08

Right. Yeah, that makes sense. So at the end of the day since OHRP has now said, you know, if it’s a if it’s a local legal issue that pertains to one of the regulatory determinations that a board’s required to make, then yes, the single IRB would need to manage that but it sounds like right now what would be most helpful is to have, a list of examples of what types of things OHRP is thinking of because right, because the types of legal things that you might encounter or that could impact one of these determinations is huge. So yeah, So just a little bit more guidance there would be helpful, I think, as well.

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I agree.

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Wonderful. Well, thank you so much, Jenni, for joining me for this timely and interesting conversation. I’m so happy that we were able to connect and get into some of the nitty gritty about the single IRB mandates and I really appreciate your perspective and your examples here, and I think it’ll be really helpful as well for folks in the community who are trying to wrap their heads around what it means to have you know FDA and HHS and within HHS NIH have these single IRB mandates moving forward.

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Thank you so much for having me. This really was a great conversation, and I am grateful for the opportunity. Thank you so much,

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absolutely, So that’s all for this week’s episode. Thank you all again for listening. If you enjoyed today’s episode, keep a look out on Advarra’s Social channels and on Advarra.com for our next episode.

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