Episode Transcript
Hello and welcome to another episode of TransPerfect LifeSci Talks. Today, I'm delighted to introduce Dr. Elin Haf Davies, the CEO and founder of Aparito. Dr. Davies got her Ph.D. At Great Ormond Street Hospital and has regulatory experience in the MHRA and EMA. Aparito was founded as a tech solution that will contribute to patient environment and the drug development pathway. It has completely transformed the way clinical trials are studied. She specializes in orphan drugs and rare diseases. Elin, welcome.
Thank you. Really happy to be with you.
So let's jump into rare diseases. We have so much data around executing studies for adults, but would I be right in saying there is kind of a lack of some data for rare diseases for pediatrics?
Yeah, it's been an interesting challenge for the rare disease and pediatric space. And children have really been the neglected orphans in this space. The orphan regulation when it came into force was fantastic in promoting that interest in the high unmet need and the opportunity to contribute to the quality of life of people living with rare diseases. But unfortunately, pediatrics as a whole have not benefited from that. And despite the pediatric regulation, we've not necessarily seen pediatric clinical trials happen and the evidence to support pediatric care transform as much. We are obviously understanding that most rare diseases or orphan drugs are also for pediatrics. And that is an area that has had maybe a difference where the intersection between orphan designation and pediatric indication overlap. But overall, I would say the pediatric population still are very much neglected orphans in the drug development space.
And, in the clinical outcome assessment area of pediatrics, there seem to be so many nuanced different things to consider. I mean, w, first and foremost, we're getting data from a proxy, from perhaps a guardian. Secondly, we're often getting information that is, if you look at certain diseases - Duchennes is a great example, but we're looking at gait and speed and the shoulder movement to get themselves supine and erect – capturing that data is actually difficult and it's not traditional. Am I right in saying there's a whole different mindset required?
Yeah, and if I look at pediatric clinical trials when I did my first ever pediatric clinical trial, it generally looked that it was a protocol that had been designed for adults and somebody had gone in and just done a word replace of adults to child and just ran with it. And that's still true in terms of the number of venipunctures for PK sampling, or the number of painful assessments that children are expected to do, completely forgetting the amount of total blood volume they've got circulating in their bodies would be an issue in those factors. And Duchennes is an example where an endpoint developed for adults in cardio-respiratory was sort of sabotaged, if you like, and used for a pediatric indication.
I call it reverse engineering. And we see the same, sometimes, we see the same with dosages, where a dose for an adult, they'll say 'well let's just reduce that for a pediatric' rather than a bespoke – I'm not saying it happens often, but rather than bespoke, study for what would be the correct dose for at that.
Yeah. And, there has been some improvements in sort of the PK/PD modeling at least, so that a pediatrician is not left to completely second guess what dose to be prescribed off label based on sort of halving the child's weight aspect. And we know that that has led to significant either under-dosing or overdosing, and the sort of side effects that's involved in it. And, to give credit to progress in the field, sort of the PK/PD modeling is one place where dosing is at least getting a better indication. But the clinical efficacy, evaluations is still an area that's massively under-invested in from a pediatric point of view.
And that would lead me on to my next question – do we need to design new endpoints for children first and foremost, rather than this reverse engineering?
Yeah, I mean my passionate belief is that actually we should always start with the child and develop endpoints that are child-friendly and then that could carry on being meaningful throughout childhood, adolescent-hood and into adulthood rather than trying to reverse engineer it. Because if you think of walking, eating, talking, social play, these are critical activities of daily living that are important in childhood and adulthood. And could be translatable throughout that sort of lifelong movements and even into elderly care. And, for me, looking at it with the child's view would make it simple, easy to use. I would think even adults would prefer to have passive friendly accommodating assessments rather than what they're currently sort of having to undergo in clinical assessments.
And that speaks to the burden on the child itself.
I mean there were so many clinical trials that we did 18-20 years ago where the endpoint was painful, it was invasive. It was embarrassing. And it required hours of attention and cajoling the child to comply and therefore the data is really dubious at that point when the child is stressed, in pain, fatigued, and had enough. And even to go back to the six minute walk test, if you are an eight year old child who's on steroids, potentially with some behavioral – six minutes is a long time to kind of pay attention and to follow the instructions. And therefore it's significantly impacted by other aspects other than disease severity.
That's a very interesting point. I never think about that. Like simple things as the physical duress of doing something like that for these patients, these children that are already compromised in some way. I never thought about that sort of burden. I'm always thinking about the pain that the patient has to go through during the treatment. Very interesting.
There's some really interesting research that sort of shows that if you bribe a child with money and ice cream, you can get them to walk further in a six minute walk test that if you don't bribe them with ice cream and money. And when we're looking for 30 meters difference in a clinical effective sort of treatment, that's a lot of influence and noise on your endpoint.
Well, the things we do to get the data. So I guess my next question then is what's the next thing that needs to happen in childcare, in child health and rare diseases?
Yeah, I think for me, we're in a post pandemic world where healthcare resources are really scarce and we likely should face other pandemics, other issues that are impacting on children, adults, rare diseases and common diseases. And to sort of separate out these aspects individually is gonna carry on causing friction and delays in accessible healthcare. And so flipping it on its head and sort of priority in child health in terms of the endpoints, the study design would ultimately be benefiting adults and future generations too. And making all clinical trials child-friendly makes them adult friendly. But also, allows us to ensure that we have a healthy and economically productive workforce for the future and the children that are coming through.
I think that's fair. You actually mentioned – you just pricked my interest. You mentioned the pandemic. We look at the vaccines now for Covid-19 in a pediatric setting. And I was rather actually very pleased to see that there were particular bespoke studies for pediatrics rather than 'let's just dilute the dosage.' Let's just model it down. It was actually proper pediatric studies. Do you see that as the future?
So, when the pediatric regulation came to force in Europe, one of the biggest successes of it was that there was a change in mindset that we should protect children through research, not protect children from research. And the sort of old mindset of 'don't use my child as a Guinea pig, you're not gonna put my child to untested medicines.' Is sort of, although conspiracy theories and anti-vaxxers aside, it is sort of a better understanding of how research can benefit care and benefit outcome. I think it's all to do with proportionality, so going back to my point, you are not gonna ask a three-year-old to do a phase 1-P case study that we're gonna draw bloods every 15 minutes because we're academically curious to see what's needed. And with advances such as the digital twin extrapolation and modeling, you really don't need to do the full-on invasive clinical trials in adults or children.
To be honest. We should be looking at more innovative ways of bringing safe medicines. And, the high costs of developing medicines, the high failure rates in developing medicines is, at some point, somebody's gonna say, why are we still doing these things in the same way expecting a different result, and why we not sort of doing it? So there is a risk of changing the way we do things because you've got patient safety. But equally we know that the current way's not working and therefore at some point we need to adapt these modeling, extrapolation, digital twin approaches to only be doing the right research for the confirmatory data that we need.
Probably off topic ever so slightly, but if you look at the criteria for adult studies, it's very stringent. We're looking for super patients. When we do that in a pediatric session setting, we can't really be as stringent, can we? We can't really have the same kinda criteria, can we?
What do you mean by, sorry, I I maybe missed that sort of when you saying the, the high criteria for,
For, for inclusion in a study. Um,
Yes. So inclusion criteria is a really interesting one. And, I think that's where maybe more of a real-world pragmatic study design makes sense both for adults and children. And again, if we go back to the global health impact, the constant challenge that we have is that the clinical efficacy identified in a very homogeneous, tight inclusion criteria from a study never ever translate to the real world effectiveness of a world population. And, therefore, we never really comparing like-for-like, anyway, and maybe that it is a question of are we needing a different approach to demonstrate efficacy and safety that can be translated to real world effectiveness?
To be honest, that's my hobby horse. That is one of my hobby horses. And I do think that we definitely need a different approach. Definitely we need to have a more real-world evidence approach. Definitely. Elin, thank you so much, I really appreciate your time here. Dr. Elin Haf Davies is the and founder of Aparito Please join us next time on our next episode of LifeSci Talks. I'm Mark Wade, Global Practice Leader for TransPerfect. Thanks.
