TRANSCRIPT
Welcome And News Lineup
Deborah Borfitz
Hello and welcome to the Scope of Things podcast, a no-nonsense look at the promises and problems of clinical research based on a sweep of the latest news and emerging trends in the field, and what I think is worthy of your 30 or so minutes of time. I'm Deborah Borfitz, Senior Science Writer for Clinical Research News, which means I spend a lot of time with my ear to the ground on your behalf and a lot of hours every week speaking to top experts from around the world. Please consider making this your trusted go-to channel for staying current on things that matter, whether they give us hope or cause for pause. In a few minutes, I'll be speaking with Florence Mowlem, Chief Scientific Officer at uMotif, about overcoming the many patient retention challenges in pediatric rare disease clinical trials. But first, the latest news, including the possibility of a probiotic for preventing immune system disorders in babies, misunderstood mechanisms of body weight regulation, a promising primary care-based weight management program, the possibility that GLP-1 drugs can benefit the brain, how patient-reported outcomes can improve clinician-adverse event reporting, and a discovery to reimbursement model for cell and gene therapies. Researchers in Denmark have been investigating specific vividobacteria in the gut of infants, which produces a metabolite that dampens immune responses to allergens and could be used as a probiotic supplement in the first months of life to prevent asthma and allergies. Results emerged from an analysis of stool and blood samples from three large birth cohorts in Sweden, Germany, and Australia. It was also found that natural mechanisms exist to help prevent the development of these diseases, since infants born vaginally, who were exclusively breastfed and had contact with other young children during early life were more likely to acquire these beneficial bacteria. While a preventive probiotic may get to the market within a few years, it'll take much longer to run the trials required for a drug treatment. Two competing theories exist about how body weight is regulated, one holding that each person has a biologically determined weight and the body defends against excessive increases or decreases, and the other that individuals have a lower and upper limit and the body only reacts when weight falls outside that range and is therefore influenced primarily by lifestyle and environment. Pennington biomedical researchers examining the matter found these set point and dual intervention models predicted different metabolic and compensatory responses in people with a low body weight in response to prolonged fasting or overfeeding. They conclude that further studies are needed to better understand the mechanisms of body weight regulation, so researchers embrace the correct strategies when evaluating new obesity treatments and interventions. On a related note, in a large pragmatic clinical trial, researchers at the University of Colorado School of Medicine found that the individualized weight management process they created, known as Pathway, changed the trajectory from weight gain to weight loss over 18 months and increased the likelihood of a patient receiving weight-related care by 23%. Pathway enables primary care staff and patients to prioritize weight management by offering specialized clinic visits, where this is the sole focus. The program was implemented at UC Health's 56 primary care clinics in the state, reaching more than 274,000 patients in the pilot, and is now being eyed by obesity experts as a standard of care with more widespread adoption across the country. Popular GLP-1 drugs used for treating obesity and diabetes, as well as DPP4 inhibitors, are two classes of medications that a large McGill University study has found to be associated with a reduced risk of dementia, adding to growing evidence that these incretin-based therapies have protective benefits for the brain. Importantly, the study controlled for diabetes severity, a major predictor of dementia on its own. Researchers say longer-term studies are now needed to confirm the results, including in people now using GLP-1 drugs for weight loss. A large multinational study provides clear evidence that patient-reported outcomes provide value in the evaluation of the side effects of cancer treatment, and that integrating this PRO data directly into clinician assessments can measurably improve the reliability of adverse event reporting and clinical trials. Previous research has shown considerable variation in side effect grading between clinicians and oncology studies. The randomized controlled trial enrolled more than 1,000 adult patients with any cancer diagnosis receiving chemotherapy, immunotherapy, or radiotherapy with access to patients' self-reported symptoms limited to the intervention group. Overall, inclusion of the PRO data improved consistency for 13 of the 17 symptomatic adverse events assessed. And finally, scientists in Sweden have created a new discovery to reimbursement model for shortening lead times and reducing the cost of bringing cell and gene therapies to market. If a promising therapy is to reach patients, the development must be attractive not only to academic researchers, but also to healthcare providers, investors, and industry. The model has all stakeholders working in parallel and in an integrated way right from the start and recognizes that hospitals are both a user of the therapies as well as part of the production chain. A cell and gene therapy navigator tool follows a project's technical, clinical, and commercial maturity simultaneously to quickly identify imbalances and future bottlenecks. The model could serve as a template for groups in other regions and internationally. As a reminder, links to the articles, studies, and press releases referenced in this month's news segment can be found in the show notes. It is now my absolute pleasure to bring in Florence Mowlem for a chat about the key retention challenges and best retention solutions when conducting pediatric rare disease trials. Welcome to the show, Flo. Thanks for having me. I'm looking forward to discussing this topic with you today. Excellent. So much. So so happy you're here. But why by way of introduction, I think it's important for listeners to know that you are an expert on the electronic capture of clinical outcome assessments or eco as it's called, and you have devoted yourself to advising and guiding organizations on digital methods for collecting patient-reported data, which involves the use of technologies like mobile devices, software platforms, wearables and sensors, and interactive voice response systems. Are pediatric rare disease trials your specialty flow or just an area that requires more attention due to the unique challenges here where maybe eCOA can step in and fill the gaps?
Why Pediatric Rare Trials Need Flexibility
Florence Mowlem
Yeah, so I would say my specialty is definitely eCOA in general. And so these are electric, as you said, electronic methods of capturing their clinical outcome assessments. And these are measures of how a patient feels, functions, or survives. And these are essentially questionnaires that can be completed by a clinician, the participant themselves, an observer, such as a caregiver or a partner. And we follow a process of how we implement these. They're normally developed on paper. Now we know that electronic data capture can offer many benefits. And so, yes, eCOA in general and at uMotif, we would support clinical trials in any therapeutic area. And so I would advise across any type of clinical trial. But what I do really enjoy and like to focus on is sort of specific areas that I think require a more thoughtful or slightly different approach to the norm. A one size fits all approach is definitely not going to work across all trials. And I think pediatric rare disease is a perfect example of this. It's also where I kind of like to focus my thought leadership work. So thinking about trying to solve some of the more complex scenarios that we encounter in data capturing clinical trials, where driving innovation, I think, is really needed and taking into consideration how we can really capture the best data, whilst also ensuring the flexibility that's required in pediatric trials, specifically in rare disease trials, is definitely one of those areas. You've got a lot to balance. You've got the participant and the caregiver experience, the burden on the site of conducting these trials, you've got the regulatory requirements. And as we're starting to see an increase in trials in the area of pediatric rare disease, we really need to start paying more attention to the methods that we're using to capture data in these trials and how we can best support them.
Choosing The Right Digital Tools
Deborah Borfitz
Okay. Now I do want to focus just for a moment on the technology piece. There is an almost overwhelming variety of digital technologies out there that could conceivably be employed in any one study. So I'm curious how do you recommend companies go about deciding on the type of solutions to employ and how to vet potential technology providers?
Florence Mowlem
Yeah, you're absolutely right. There are a lot of technologies out there, and I think we're just seeing more and more. I would say when I'm advising that it and about selecting digital methods to support a trial, that really pay consideration to the end-to-end flow of your trial, of your work processes and the user journey. There's a lot to juggle. You want to capture the most robust data. And so the systems and solutions we use should be aiming to ensure that we are capturing that robust data, but also making those workflows and tasks as easy as possible and as streamlined as possible for the sites, the caregivers, the participants, that, you know, all of those people who are involved in a clinical trial. And also encourage them to really, really think about what are must-haves and what are nice to have, and try and put themselves in the position of the participant or the caregiver or the site, and really try and consider their perspective and think about what they're going to be experiencing when they consider the potential burden and obviously the potential benefits of using any of these digital technologies. And it will really depend on your trial and thinking about your trial design about whether certain digital technologies are going to be appropriate and suitable and bring that benefit or not.
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Deborah Borfitz
Yeah, you have often made the point that even the best eCOA system won't generate high levels of compliance if the study itself is poorly designed. So, in terms of pediatric rare disease trials, where do you see sponsors, study sponsors most often tripping up?
Avoid Overlong Measures And Visit Burden
Florence Mowlem
Yeah, so I think I see sponsors often, and for very good reason, get very worried that because of the nature of the therapeutic area, so it is rare, that this is their one shot in this trial. And so they want to try and measure as many things as possible to really mitigate the risk of not finding a signal. And this can often result in incredibly long site visits for families who already have very busy and stressful lives. And when we think about the actual measures, so the clinical outcome assessment measures that would be being used. So whether it's often in these trials, it would be the caregiver who would be responding to them. Quite often we see that these measures are incredibly long. And then when you choose multiple of these, you're obviously going to have a lot of questions that are going to have to be responded to. This can be incredibly overwhelming, it can lead to fatigue. And so we're really asking a lot of participants and their caregivers, along with the sites who are conducting these visits, perhaps conducting the interviews with the caregivers or the participants, when we are essentially throwing all of these different questionnaires at them, which are very lengthy. And we have to really think about is that going to get you the data that you need? And again, it comes back to that what's a nice to have and what's a must-have? And I think following on from that and the point that you were making about eCOA systems and the levels of compliance, definitely experience as an e-coa provider, that we get asked so much about our metrics around compliance with data capture. It's probably up there with one of the top questions that we get asked. And I think a lot gets put on the eCOA provider as having full responsibility for that. But we cannot solve for a badly designed measure, a really long measure, multiple long measures being implemented in the same trial, one after the other, bad study design. We can't control compliance around those elements. And so I think, you know, we all have to work together and partner together on coming up with the best study design to ensure that we will have the best compliance that we can for that data capture. And we know that electronic leads to better levels of compliance, but we can't guarantee it in the face of a poorly designed study.
Start With Endpoints And Relevance
Deborah Borfitz
Yeah. And I think you may have already sort of addressed this to some degree, but I want to dig in a bit more. You know, kids with rare diseases may have a broad range of health status characteristics that might logically seem worthy of capture, but which might easily undermine efforts to sort of right-size technology use in studies. How then are sponsors to proceed? What are some specific, I don't know, advice you can throw at me here, throw at the sponsors out there listening?
Florence Mowlem
I think it's comes to that saying of start with the end in mind. So it's so important to think about exactly what you think the end intervention that you're studying is going to have an impact on. And primarily your focus should be there. So, what are your endpoints in your trial? What do you believe is going to be improved with this intervention? And make sure that that is the focus of your measurement strategy. As I said before, sponsors can get carried away with thinking, well, this might be my only shot. It's such a difficult population to recruit already in a trial. So I just want to try and measure as many things as possible. We know rare disease can be so heterogeneous in the way symptoms and behaviors are experienced and displayed, and focusing on what the majority of individuals have in common and therefore what you believe your intervention is going to impact will ensure that you are not trying to measure everything that you could possibly think could affect a given individual. Because this essentially means that you're also measuring things that would be not relevant, would be, yeah, wouldn't be relevant to a lot of the individuals in the trial. And that can lead to frustration because they're answering questions that include items and domains that are not relevant to them and end up not being relevant to the majority of individuals in your trial because you're trying to capture those things that are only impacting a very small number. Yeah. And that essentially can impact the data that you absolutely do need.
Deborah Borfitz
Yeah, good, good points here. Next, I want to turn to the role of caregivers in these trials. This is not necessarily one person, but a rotation of different family members who might be responding to questionnaires. Doesn't this create some data quality concerns? And if so, how might these reasonably be addressed?
Florence Mowlem
Yeah, that's a great question. I definitely think there seems to be two camps regarding this. So we've got some who think that any data is better than no data. So, regardless of who would be reporting on the participants' symptoms, behaviors, it should always be on observable things from the caregiver. They think anything is better than having missing data. Whereas we have others who think that obtaining data consistently from the same person is more important than having that full data set. But I think we just can't deny reality. It's not always going to be the case that a participant has a single caregiver that is with them 24-7. Even when parents are together, it's very unlikely that it's only one of the parents that is always with the child, or when you have parents that are not together, or grandparents who are contributing to childcare, or the children are in school during the day, and so on. How can we expect it to be only one person that is observing the child's symptoms and behaviors? I do think there's something to be said for the difference between measures which are more objective. So, for example, if we think about capturing the occurrence of seizures, one could argue that that is more objective data. It's observing something that is quite objective in nature and counting compared to some of the measures that we see that are asking for a rating, so how severe something is. And we know that that is different for different people. They have different levels of severity. And so if you have two parents reporting on those measures at different times, then we could expect that there could be discrepancies. However, we also have very advanced statistical methods nowadays, and so it is something that I believe that we can account for. And I think as long as we're thinking about all of these things up front during the protocol design phase and when we're developing our statistical analysis plans, then we can really account for these different scenarios.
Embracing Justifiable Flexibility
Deborah Borfitz
Perfect answer. Thank you. And I'm sure AI is somehow involved in the mix there as it seems always to be or or could be employed. Would that be the case, by the way? Is that something where AI has a role?
Florence Mowlem
I'm sure it could do. I'm sure it's got a role in everything, as you said. But I yeah, I definitely think with statistical analysis, we'll start seeing more of the use of AI.
Deborah Borfitz
Well, I'd like to end with a question I often ask some version of at the end of my interviews to be sure everyone's clear on your big take-home message. And well, here it is. What is it that you would most like clinical research professionals to walk away from today's show knowing or ready to do to improve the viability and success rate of pediatric rare disease clinical trials?
Closing Thanks And Listener CTA
Florence Mowlem
So I think as an industry, we tend to be very conservative and we can get stuck in our ways, be quite resistant to change, and not always innovate in the way that we should, or we innovate slowly. And there are obviously very good reasons for this. We work in a very regulated industry where we can't deny the importance of what we're doing. We're evaluating interventions for the treatment of serious health conditions and participant safety and well-being is paramount, as well as ensuring that the data we're collecting is robust to meet the required standard to assess this efficacy. You know, all of this is critical, but we do need flexibility, and we do know that a one-size-fits-all approach doesn't work for all scenarios, and it can actually have a negative impact. So I think the one thing I would like people to think about is that individuals for whom this trial truly is their day-to-day. So the participants, their family and friends, the site personnel, don't add more to their lives than is truly needed for your trial. Be comfortable with allowing justifiable flexibility to make their lives and participation easier wherever possible. And I think that really, well, a lot of it comes down to don't measure what you don't need to. Don't measure things more than you need to. Don't ask these people to respond to more questions than you need them to, don't make them come to sight more than they need to. And essentially don't add more complexity to electronic systems to account for all of the possible scenarios and essentially end up placing burden on everyone.
Deborah Borfitz
I think I have heard this in one way, shape, or from various people, probably for years now. This this now specific to pediatric rare disease, clinical trials, of course, but Sage advice nonetheless flow, and we really can't say any of this enough anyway, can we? These messages sink in and soon. Thanks for taking the time to chat with me from across the pond today. Really appreciate it. Thanks for having me. And as always, a big thank you to everyone out there for listening in. If you're not subscribed to this podcast yet, please consider going to Apple Podcasts and doing so right now. So you don't miss your monthly dose of news and perspectives. You'll be hard pressed to find anywhere else. And if you're up for it, I'd also be so very grateful if you'd leave a review and a rating while you're there. For more straight talk on studies involving humans, visit clinical research newsonline.com. And if you're a clinical research professional, we hope also to see you at our next Scope Conference, where we make things happen. Bye for now.