Making an IMPACT: Advancing Alzheimer’s Disease Clinical Trials Through Workforce Development and Inclusivity

Transcript

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Hello, and welcome back to Dementia Matters. Today, I'm recording this podcast episode live from the Wisconsin Alzheimer's Disease Research Center's annual Alzheimer's Disease & Related Dementias (ADRD) Research Day. The event is designed to encourage collaboration and promote scientific thought among faculty, students and researchers from a wide range of disciplines across the University of Wisconsin–Madison campus. I'm joined by this year's featured speaker, Dr. Rema Raman, a professor of neurology at the University of Southern California (USC) and the director of the biostatistics section in the Recruitment and Retention section at USC's Alzheimer's Therapeutic Research Institute. Dr. Raman is also the co-lead of the Biostatistics Unit, the Recruitment Engagement and Retention Unit and the Inclusion Diversity and Education in Alzheimer's Disease Clinical Trials unit for the NIH-funded Alzheimer's Clinical Trial Consortium, known as ACTC. Additionally, she's the co-director of the National Institute on Aging and Alzheimer's Association funded Institute of Methods and Protocols for Advancement of Clinical Trials in ADRD, known as IMPACT-AD. Dr Raman's work focuses on efficient clinical trial design and analysis, centralized statistical monitoring and data visualization, recruitment and retention science and missing and longitudinal data analysis topics. Now usually I wouldn't include such a large intro. However, I think they all are very interesting. I want our listeners to know how they sort of relate to each other because I think initially one might ask, “Well how did you get involved in such diverse areas within the field?” Dr. Raman, welcome to Dementia Matters. I hope you're enjoying your visit to Madison.

Dr. Rema Raman: It's been a fantastic visit. Thank you so much for having me on today.

Chin: Well to start, I'd like to learn more about this work you do at the Institute of Methods and Protocols for Advancement of Clinical Trials in ADRD, or IMPACT-AD. This is a comprehensive program founded to train the next generation of ADRD clinical trialists. As co-director, your goal is to educate and promote diversity among research professionals and future principal investigators in Alzheimer's disease and related disorders research, so if you could share with us why you chose to work in this area, how it potentially affects patients their loved ones in the future and, frankly, how it relates to all the other things that you do within the field.

Raman: Thanks Nate. One, we use a lot of acronyms in Alzheimer's disease, and in fact AD is one such acronym. It's a training program, and one of the reasons why we started believing that this was an important element to add to the research portfolio in general is that our trials – and when I talk about our trials I mean both Alzheimer's disease or AD trials as well as Alzheimer's disease and related dementias and ADRD trials – are a field. It's like a field unto itself. It requires certain skills. Things that are unique, I think, to our trials are our trial designs, our outcomes. We use cognitive and functional outcomes. We have novel markers now as outcomes. We also have recruitment and retention challenges because we want to have inclusivity in our trials. We also have to recruit dyads into our trials because our trials require both the individual, but also a study partner. It's not just one person; it's two. Those are unique challenges to recruitment retention. We also have unique issues around ethics, whether it's disclosure, biomarket disclosure or informed consent. These are elements around trial design that are unique to AD and ADRD trials, and both scientists who are leading these trials and the research teams that are conducting these trials all need to be trained in these unique aspects. That's sort of how this program came together. The other element of clinical trial design and conduct is the fact that you don't do it by yourself. You do it as a team, so team science becomes important from a science perspective and from a design perspective. You've got clinicians, you've got neuropsychologists, you've got imagers, you've got biomarker experts, you've got statisticians – all needing to work together. This group then has to work with trial operations research teams and regulatory specialists all collectively making something happen. That requires specific training. It requires an attention to these details. I think that is the need, and these are not really taught in traditional medical schools or biostatistics programs. We felt that there was a space for such a program and a need for such a program in the field of AD and ADRD trials.

Chin: I mean, as you explain it I feel overwhelmed thinking about everything that goes into conducting a good trial. Whether the result is what we want or not, just to do it properly feels unbelievably complex with multiple moving parts. Yet when you say to someone, “Oh, clinical trial,” I think most people think, “Oh, okay show up, get some sort of drug and be watched,” but it's so much more to that. Before you had this IMPACT-AD, was there much training for young trials or older people who wanted to do trial work?

Raman: Yeah, that's a great question. I remember how in a certain sense how I was trained I was trained on the job. You have mentors, you have senior investigators, senior research staff who are part of the teams and you sort of learn and go along the way. Now as a field we have – we're making movements so rapidly. We've got new drugs coming that are being approved. We've got new biomarkers. We've got the need to make our trials more inclusive. We've got the workforce, the regulatory oversight that is becoming much more important and critical. It's no longer easy to just learn on the job. It's important to have some formalized training in building that network because you're never going to do it alone; you've got to do it together. It's also about building a network. Part of what we're trying to do is also build a clinical trials network through the alumni scholars of this program to be able to develop ideas and work together to conduct trials of the future.

Chin: It's a heavy lift. There's a lot that goes into this. Not only financial investment, but then the time of the people doing the work, the time of our participants coming in, and then also this pressure, probably from our society, to say, “We need successful trials. We've waited a long time.” I know some of them are now successful. It makes sense to me what you do. The study has to be properly built before it can be done.

Raman: Right, you've got to know how to design the right trial based on evidence and information that exists and also new information that's coming. Then you have to actually conduct – as you said – the right trial, because at the end of the day you want to be sure that whatever your result is that you can stand by that result. You may not – like you said – like it because maybe the intervention doesn't work, but you have to be confident that you can say that the intervention doesn't work. You still learn something. You learn that, “Okay that doesn't work. Let's go on to something else.” What you don't want is to end up with the question, “Does it work or doesn't it work?” and that's why rigor in trial design and conduct becomes important. That just doesn't happen accidentally. It's done intentionally through trained staff and researchers really working together to make sure that it happens.

Chin: Each clinical trial is likely different, so you can't just copy what someone else has done. You have to be specific to your population, to your outcomes. I appreciate you saying that. The outcome matters to everyone, but that's going to be different depending on what people are looking at. You really have to start from the beginning almost with every clinical trial. Maybe learning from others but it's not like you can just take some page out of a playbook and just do it.

Raman: That's right, because in one way, it's right, in that yes, every trial is different. Who you're studying, what the intervention – if you're talking about a medication, what is the biology behind it? What is the target engagement of that particular compound? Then in some aspects things are very similar, in that the rigor element is the thing that you can't compromise. There are certain aspects of design that ensure that rigor, and so that's where training comes in. You've got this underlying sort of set of principles that are required to ensure rigor reproducibility, to ensure data security, then, on top of that safety, to ensure participant safety. These are all non-negotiable. Then you have the modifications that come with the particular intervention that you're studying, who you're studying, at what stage of the disease, where is it being studied. Those are the changes that happen, but the fundamental principles are sort of your bedrock of rigorous trials.

Chin: Every trialer should know those.

Raman: Right, exactly. Exactly

Chin: Well one thing that's also coming up that's pretty consistent is the importance of representation. Can you explain the work you do surrounding recruitment and retention science and then share any milestones or key outcomes in your research, particularly if anything surprised you in your research?

Raman: The part around inclusion is becoming really important for multiple reasons. You kind of – we moved away from using the words like representation and moved towards inclusion because what we're trying to do is make sure that anyone who's interested in being a part as a volunteer in trials have an opportunity if they're eligible for the trial based on the criteria. I think from a bigger perspective the need for inclusivity in our trials is to drive an understanding of whether the safety and the efficacy profiles are similar or different between the different important subpopulations. You can't really say they are or not but at least you can see signals that indicate that they may be similar or different. My work in recruitment and retention sort of stemmed from that need. How do we make our trials more inclusive? That's really what our team has been working on. We're taking sort of two different approaches. One is – I'm a statistician, data means a lot to me – kind of take an evidence-based approach data driven approach to understanding any problem. To find solutions you need to know what your problem is, and so we've been collecting data at every stage of this process: who's coming in, who's not coming in, who's being considered for our trials, who's not making it through the screening process. Then once you monitor and you understand these reasons for disproportionate screening, then you can go in and start creating strategies that would allow us to get more inclusive if that's wrong and addressing these gaps. That's sort of one way in which we've been addressing it. The second is really starting to take a much more evidence-based approach to recruitment and retention science, trying ideas. Do certain recruitment strategies work for certain communities? Is social media a better approach to reach certain communities compared to earned media? These are all questions that you can ask in a much more rigorous format so that you're adding to the evidence in this space and to the literature. We do randomize trials around recruitment, we embed it in the screening process. Does financial incentives work better than just messaging or information? These are kind of ways in which we're trying to add to the evidence base so that everything that we do we take a data-driven and evidence-based approach so that we can then scale, because you try it out in one population or one region of the country. Question is if it works, can you now try it at a national level or can you go to another population of interest? That's sort of what we've been trying to do. What has surprised me is that we have a slogan in our team and that is – to conduct clinical inclusive trials, we've got to take an equitable approach to recruitment and retention. I think that is something that I've learned over time is that it's – to reach communities that have traditionally been underrepresented, it requires us to make the effort to build those bridges between community organizations and individuals who have access and trust with those communities with the trialists who actually conduct these trials, who have the expertise, who have the staff, who have the teams to conduct these trials. You've got to build that bridge and the bridge has to be a two-way bridge. That takes time, that takes resources and that takes sustained resources. That was – I mean I kind of always knew it I think, but it's really becoming more evident to me how important it is, that bridge with the community and the trials as opposed to us doing it in silos.

Chin: Yeah and we see that here in Wisconsin. Many of our Black participants have come in saying, “We want our experience to be reflected in the data you collect.” When it comes to clinical trials, when it comes to medication pharmaceuticals, they want to know that their communities have gone through the trial so that if it does ever reach the clinic level that it would actually be meaningful to them or, at least with more certainty, that it would be meaningful. You're right we can't answer all of the questions with the data, but it took that scientific approach that you're having in order to even identify the importance of this.

Raman: Right, and this goes back to the training. That's why I think all of these are so related is the need for a workforce, whether it's the leadership of trialists or the team that actually conducts the trials. It's important for that group to reflect the lived experiences of the individuals we are asking to be part of our trials. If there is a disconnect there it's going to be a lot harder for individuals to believe that their lived experience is of value to the research teams. I think that's the other thing we're trying to change through the training programs is to make sure that the cohorts are a lot more reflective of the diversity, both demographic and lived experiences geographically, among individuals who we are trying to reach. I think that that is an important element that I think I’ve started recognizing how important it is, which sort of ties back to why workforce development becomes so important.

Chin: Yeah. Now later today you're going to give a talk as our featured speaker for Research Day, and it's entitled, “Accelerating the Impact of Next Generation AD/ADRD Clinical Trials Through Inclusion and Workforce Development.” Now I know you can't truly summarize your talk in a matter of minutes, but if you could explain or share some of the significance or some of the things you're going to talk about for our audience.

Raman: Absolutely, I’d be delighted to do that. I just want to set this talk in the context of what I think are three things that have happened in the last several years in the field. The first is this fact that we are moving closer towards prevention, secondary prevention. We already have trials in the preclinical Alzheimer's population looking at trying to reduce the levels of amyloid in the brain, but even moving earlier in the process of even before we get to that stage. We're moving slowly but steadily in that space. Second is the development of blood biomarkers. It's completely – in my mind – changed the framework of how we do trials, because now we can use it to facilitate earlier screening. Also as an outcome, which can be done and collected more in the community without these research teams. It can also be done faster. It can be done in a much more safe environment. All you need is a blood test, so it's completely changed the framework. Third is that we have a drug for early Alzheimer's disease, an approved drug that is being covered. To me, that's also been a game changer in that all of this work by all of these trials in the last decade is now culminated in a disease-modifying therapy. It's not just taking care of disease but actually modifying the disease. That's huge, and it means that the next generation of these trials are coming. What I was hoping to do in today's talk is really set that framework around what has happened – the excitement in the field right now – where we are headed and talk about some of the work that we're doing to get us there, talk about the training programs and hopefully sort of spark that excitement about wanting to become part of this network of researchers trying to find new safe therapies for this disease.

Chin: Well I can't wait to watch your talk. For our listeners for the podcast, it will be available at some point after your presentation, but I want you to put on your mentor hat now. What advice would you give today's students and early-stage researchers about following a career path in Alzheimer's disease and related disorders research?

Raman: That's a great question. I'm going to put on my quantitative hat on this one. I'll leave the clinical one to you, and say several things. I would say, as a scientist, the need to test and evaluate objectively is probably the most important thing you can do, so ensuring that you are recognized bias in the work – whether it's your design, whether it's your conduct, whether it's your own inherent bias – is really important in anything that we do in science. The second is the curiosity. That's going to be what gets you to the next level is just being curious, being persistent. If it's an idea that seems right to you, keep pushing. Sometimes you're going to have to challenge the status quo to get there. We've been doing this for 20 years within a certain paradigm. That paradigm is shifting, and so the ideas have to shift. You're going to have to start thinking about the status quo being really something that got you here, got us here, but now we might have to look at it in a different way. I would also say that team science is the way of the future. You can't do it in silos anymore. We've never been able to but we definitely can't do it right now. Building those skills – essential skills around communication, around EQ, around cultural quotient, understanding cultures because we're now also going global – that's going to be really important. Finally, to become technically savvy. There's a lot of buzzwords being thrown around with big data and artificial intelligence. Just recognize what it does and what it does not do, what its strengths are, what the use of these technologies, what the strengths of these technologies are and what the limitations are. What classical statistics is versus what machine learning does. What is prediction versus what is inference. What is the best approach to use is dependent on the problem that you're trying to address. It isn't the other way around. Your problem drives your research, not the other way around. That's sort of what I would say is the curiosity. Most of all, consider trials as a career choice. It's a great space to be. It's a very exciting space to be right now as we develop new drugs, combination therapies. We're attacking it from every which way lifestyle trials, drug trials, device trials combinations of all of these. This is a really exciting space to be, so I would say consider moving into clinical trials as a career choice whatever your area of specialty and background might be.

Chin: Well that's very empowering. I'll say to me, mastering the things you just said and being aware of those means you're going to develop meaningful, valid clinical trials, which means we then get closer to the outcomes we care about but it starts with that. On that note, where do you see the field of Alzheimer's disease research in the next five years?

Raman: I'm really excited about where I think we are headed. We've just started. We have our first drug. It's the first generation of treatment. It's not the final destination. We are working on more treatments. We're working on better treatments not just for Alzheimer's disease, but for all related dementias as well. As the biomarker space, as that work develops we might have ways in which to identify individuals who sort of span the spectrum of AD and related dementias and allow drug development in each of those areas. Most of all I think, from a personal professional standpoint, what I'm most interested in is really building a global clinical trials program for pharm trials – pharmacological trials. Really being able to conduct these trials in all parts of the world including lower- or middle-income countries, so that we can really evaluate – we can conduct larger trials. They can be done faster, and the inclusivity is just happens by default because now we have communities that are reflected from all parts of the world. That's really my personal goal and professionally my goal is really I see global prevention trials as the key to finding treatments. I think that is what is going to change public health landscapes both for families and individuals, because we do it through improved health equity.

Chin: Well I sure hope you succeed.

Raman: Thank you.

Chin: Thank you, Dr. Rema Raman for being here today on Dementia Matters. Again, for our listeners we will have eventually her presentation available online.

Raman: Wonderful, thank you for having me.

Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, Google Podcasts or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app – it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin–Madison. It receives funding from private, university, state, and national sources, including a grant from the National Institutes on Aging for Alzheimer's Disease Research Centers. This episode of Dementia Matters was produced by Amy Lambright Murphy and Caoilfhinn Rauwerdink and edited by Haoming Meng. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.