Addressing Challenges in Management of Adverse Events in Clinical Trials Involving Older Adults with Serious Illness

Join Dr. Mike Steinman, from the University of California, San Francisco and Abigail Baim-Lance, PhD, from the Icahn School of Medicine at Mount Sinai, as they discuss how existing procedures for serious and non-serious adverse events (SAEs/AEs) are not always appropriate for clinical research involving older adults with serious illness. They also explore an alternative approach to defining, monitoring, classifying, and reporting adverse events in this population.

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Transcript

Michael Steinman, MD: Hello, I'm Mike Steinman. I'm a geriatrician and a Professor of Medicine at the University of California in San Francisco and the San Francisco VA. And I am very pleased to be here with Dr. Abigail Baim-Lance, who is an anthropologist and Assistant Professor in the Department of Geriatrics and Palliative Medicine at the Mount Sinai School of Medicine. And Abigail is gonna be sort of talking about the module that she co-authored with Katelyn Ferreira. So today we're discussing the key points from that module, which is around Addressing Challenges in the Management of Adverse Events in Clinical Trials Involving Older Adults with Serious Illness.

So Abigail, thanks for being here. Do you wanna take a moment to introduce yourself. 

Abigail Baim-Lance, PhD: Sure. Well, thank you for having me. This is a great opportunity to talk about some work near and dear to to my heart. As I think you know, you very nicely introduced, I'm trained in medical anthropology and do research in the space of health services research [01:00] and implementation science with a focus on issues related to individuals aging with chronic conditions and complex care needs. And I work across the Icahn School of Medicine, Mount Sinai in the, in the Department of Geriatrics, as well as I'm affiliated to a, a Geriatric Research Education and Clinical Center at the Bronx VA. 

Michael Steinman, MD: So, getting into the content of what you had sort of written about, just kind of big picture, when a person in a clinical trial has a serious adverse event, for example, they die or maybe they're hospitalized, what is the usual process by which those events are reported?

Abigail Baim-Lance, PhD: So what has become a sort of standing process or usual process is for an individual where that event has occurred for a, an investigator study team to document that occurrence. Either as a non-serious adverse event or an, or a serious adverse event. [02:00] Usually hospitalizations and, and deaths are classified as, as serious adverse events.

And those events would be reported to a data safety monitoring board , a DSMB, and to a, an an IRB on the other regulatory body that oversees clinical and human subjects research. That reporting could happen in an expedited fashion if those events seem to be emergent and problematic, that should be looked at quickly. There are other reporting processes that would be more sort of on a routine, more aggregated basis. So those are the two kind of categories. If, if the events meet the definition to be monitored. 

Michael Steinman, MD: So you just just described kind of the normative process that's evolved, but I'm curious, can you explain like how does this paradigm about what's normative really not work in the context of trials that involve older adults with [03:00] serious illness? And why is it that we might need a different approach for those kinds of trials involving that study population? 

Abigail Baim-Lance, PhD: Right. So that normative approach that I was describing assumes that those events are out of the ordinary. They are unexpected and on the face of them, problematic and likely linked to or associated with the clinical trial intervention or the mechanism that's being tested out in the study. And actually in clinical studies with older, seriously ill populations, many of those kinds of adverse events are happening regardless of their participation in research studies. They're more common and frequently occurring, and their occurrence may not be related to their involvement in the study. These events can happen more frequently because of the nature of the conditions and the [04:00] populations.

We also know that research taking place around individuals who are seriously ill and older, often the research subjects are not even those individuals. They may be caregivers or individuals who are- clinical and more organizational research studies. And so those kinds of of studies may also have adverse events happening to patients kind of around them. But the actual interventions themselves and the clinical trials themselves aren't targeting those patients. They're actually trying to develop interventions and supports for, for other people like those caregivers and so the typical reporting process would either be perhaps not associated with the interventions or they might not be relevant to the purpose of the, of the research studies, the interventions under study, and the populations that are meant to be served.

So we determined, we, identified the problem of an [05:00] implausible relationship between serious adverse events. And the interventions or the studies that are taking place, that's like one class of problems that we determined. 

Michael Steinman, MD: Just sort of broadly speaking, like what's the problem with just going with a normative approach?

So yeah, a lot of these events, you know, when people who are old and serious illness, maybe it's to study people in hospice. Yeah. We expect a certain number of them are gonna die and that's just expected and it really has nothing to do with any sort of intervention we might be testing. But what's the harm of just doing reporting of those results like we would of those events, just like you would do for any other clinical trial in a younger, healthier population? What's, what's the downside of just going with the routine process? 

Abigail Baim-Lance, PhD: Right. So many of those events that you're describing, if we think that they are alarm bells about the nature of the study, we could be reporting very frequently these single case events. And if they're erroneously related, [06:00] we're talking about a lot of effort being put out both by study teams, by administrative bodies that are overseeing those studies to look up, you know, really issues that, that don't really need probably to be tracked. So there's a, there's an efficiency issue. 

There's also some issues around really then identifying the signal. You know, when there really is a problem going on in studies and it's hard to separate out then those signals when we really should be concerned about the studies that are taking place from events that are happening that don't really necessitate the sort of traditional, normative kind of follow ups that would happen for other populations. Maybe a bigger picture also thing to flag is that what we discovered was that, and we may get into that, you know, there are ways we can change practices, but the reporting processes are often kind of normative and conventional. And there's a kind of risk [07:00] adverseness that the work that we've done has has unearthed.

And I think that part of the challenge is that investigators and researchers may become risk averse from doing actual studies with individuals who are older, seriously ill. And we may be creating a higher bar for research participation, and we may be exacerbating some inequities in who participates in research and under what kinds of conditions.

Michael Steinman, MD: You know, for an investigator considering doing this trial, recognizing those, those really harms of approaching using the normative approach to reporting, are there standards and very clear regulatory guidance about what investigators do and do not have to do about reporting in these different scenarios.

Is there like a, a handbook you can look up that just tells you exactly like in this scenario you need to do this and everyone's on the same page? Or is it just a big mess?

Abigail Baim-Lance, PhD: Right. There is some guidance out there. [08:00] There are some toolkits. You can go to the National Institute on Aging's website and find some guidance for investigators in terms of developing data safety monitoring plans, and that should also be informing how a data safety monitoring board oversees a project. 

But, we found that there are some ways we might wanna rethink some of that information. And we also found that though that information is out there, there are some tools to use in these interviews that we conducted as part of this sort of process to identify the challenges and come up with some solutions. Those we interviewed said that they couldn't really name guidance. They felt that there was a lack of guidance.

There's also a lack of guidance for individual members- you know, individuals serving on data safety monitoring boards and that sort of thing. So it does seem that while some material exists and there's certainly some regulations that one can go to, it isn't that easy to access and, and folks [09:00] out there, you know, serving in these different roles and trying to, you know, be above board with their studies and, and navigate this in appropriate ways, are feeling that there's a lack of guidance and that we could really make that much more robust.

Michael Steinman, MD: And so kinda into that breach, you and your module co-author, Katelyn Ferreira and other colleagues came up with the framework for kind of tackling this problem and helping to make some sense of it. So can you, you know, sort of tell us a little bit about the approach you developed and, and how it works.

Abigail Baim-Lance, PhD: Yeah, so we're putting forward an approach that would rely on sort of six key principles that could guide both the development of the plan, the data safety monitoring plan, which would include how to define what an adverse and serious adverse event should be in the context of the study, how and what the time scale should be of reporting. Back to that point, I was raising, should reporting be in an aggregated way or in an expedited rapid way, because there's a real [10:00] signal of concern around the mechanisms of the study. And this could also be used by those who are monitoring, the bodies monitoring the project. 

So the six sort of key principles of this approach would be to first consider the type of intervention that's being used or studied.

This refers back to the idea that there's a lot of different kinds of studies that are part of this kind of landscape of research going on around individuals who are older and seriously ill. These could be organizational studies where you're working with clinicians. They could be studies with, as we described, caregivers. So we really wanna consider the type of interventions and think about what would be appropriate as adverse events with respect to those interventions. 

We would like to encourage the use of routine over expedited reporting because a lot of these events, as we said, may occur naturally or are common and expected, so they should be reported. You know, we wanna [11:00] underscore, we really wanna promote safe research and reporting is probably really important, but it, it may be better to do in a routine way to really suss out patterns in the data. 

We wanna prioritize relatedness, so we wanna really think about what could be caused and be related to the study interventions in terms of those adverse events.

We propose subsuming what's in the land, the language of oversight. We wanna subsume expected what we expect to happen into the relatedness determination. And this gets a little technical, and maybe a little beyond the scope for this conversation. But, you know, we wanna think about what's expected, what we might commonly see, but back to that index of what we think would be related to the mechanisms of the intervention and what they might plausibly cause to happen. 

We really wanna consider goal concordance, and this is probably one of the most sort of novel areas, I think in our framework and something that also [12:00] requires some follow up work. We wanna really think about whether adverse events are really adverse to the participants of our research studies.

You know, sometimes at end of life we might want to cease treatment or we might prefer a hospitalization than in-home care. And so those might be entirely appropriate, even though , if we take these standard definitions, you know, they would be seen as adverse and problematic. So we wanna really figure out ways to think about how we can be patient-centered and really value the goals of patients and family members, perhaps, in our study measures around monitoring, and we wanna reconsider this category called seriousness.

So we really think about reporting seriousness that's appropriate. And we've developed this as a kind of decision making tree so that you would go as an investigator or someone doing oversight could go through these principles almost stepwise, and figure out through the tree, you know, what would be appropriate to report and in what timeline.

Michael Steinman, MD: Great. So [13:00] that's super helpful. So you have this tree, and if I'm understanding correctly, you have the tree, and the tree has like these branch points where you consider the type of intervention. You prioritize routine over expedited reporting where it's appropriate. You think about the relatedness of the adverse events to the intervention and whether they're, they're really were expected in the first place, in concordance of goals and whether an adverse event truly is serious from a patient-centered lens, and then people can walk their way through the tree and that it helps kind of provide some guidance about how they need to think about their reporting requirements.

Is that, is that a fair summary?

Abigail Baim-Lance, PhD: A fabulous summary, . 

Michael Steinman, MD: And where can investigators find the framework that you develop?

Abigail Baim-Lance, PhD: We have a published manuscript, which includes a visualization of this tree we're describing. So this is a paper that we published. There are a number of co-authors on this paper, so I, I cannot take credit for all this work- this is really very, very collaborative- in the Journal of General Internal Medicine, published in 2022. [14:00] Also, all of the principles and the step-wise relationship of the principles are included in the AGS/ [AGING LEARNING Collaborative] Module that I think accompanies this discussion. We would also like to develop more outreach. That's a real sort of key next step for us, is to do more consensus building education and outreach where we can disseminate this tool and other supporting tools that need to sort of accompany this so that these become really effective pieces of, of support for researchers doing, doing work in this area.

Michael Steinman, MD: I mean, it sounds just like a fabulous tool. And hopefully it will be, you know, become sort of widely taken up and becomes sort of the new standard for how IRBs and data safety monitoring plan development and other things sort of think about these issues. But it sounds like it's not quite there yet. It's just came out just this year, so you know, until the time when it sort of becomes the new standard. What advice do you have for investigators who are about to start a trial under [15:00] sort of the existing regime and how can they best sort of take these principles in a practical way to an IRB or DSMP that might not be aware of or, or have embraced those principles so far?

Abigail Baim-Lance, PhD: Yeah, that's such a great question. I mean, I, I think we hope that in the short term, perhaps this paper that we have could become an advocacy tool. If an investigator is working with a DSMB, or as you say an IRB, perhaps they could take this content with them to kind of support what we see as one of the great opportunities within the regulatory landscape, which is that there is great discretion- or maybe I shouldn't modify it with great. But there is discretion in the current regulations for investigators to be more sort of proactive and in control of the events that they would put into their plan to monitor, you know, to classify and monitor in their work. So there is space for this. You know, [16:00] we don't have to kind of rewrite the regulations to provide more of this sort of proactive sort of empowerment.

So I would say, you know, try to take this existing work we've done. And use that to develop, you know, sort of the, the stance and try to go forward, you know, and, and know that you can develop studies with appropriate measures to monitor and maintain safety. I think that's what we have to work with at this point.

And hopefully as you say, we'll be able to embed this tool more places and hopefully embed it in sort of regulatory spaces. Like I'd love this tool to at some point be available, you know, on the OHRP or the NIA toolkit websites, you know, and, and really try to, to embed these ideas there. Cause I think that's where, you know, it will start to drive real use of it.

Michael Steinman, MD: Well, may that be so! This was probably a good place to wrap up, but congratulations on really fabulous work. I think many investigators as well as regulators and IRB/ DSMPs have sort [17:00] of been craving this guidance, even if they didn't quite realize it. And so big kudos to you and the team for advancing this work and thanks for joining us today.

Abigail Baim-Lance, PhD: Well, it's my pleasure and if anyone listening would ever would like to reach out to our team with any, any thoughts or questions, you know, we're, we're just an email away. 

Michael Steinman, MD: Wonderful. Thank you, Abigail. 

Abigail Baim-Lance, PhD: Thank you so much, Mike.