Episode 2: Natural History Study
Natural History Studies (NHS) are important in understanding the natural progression of a condition. This information can then be used to predict what may happen in the future when children are diagnosed with genetic epilepsies, and are essential when planning trials of treatment. We talk with Dr Katherine Howell, the principal investigator of the international SCN2A Natural History Study.
Hosted by Kris Pierce and David Cunnington, parents of Will, who has SCN2A.
Dr Katherine Howell is a paediatric neurologist and epileptologist at The Royal Children’s Hospital, Melbourne, and a Clinician-Scientist Fellow at the Murdoch Children’s Research Institute. an honorary senior fellow at the University of Melbourne and an honorary senior research fellow at the Florey Institute of Neuroscience and Mental Health. Dr Howell’s work on SCN2A-related disorders has been important in describing their clinical features, determining a number of different subgroups (phenotypes) of SCN2A-associated epilepsies, and understanding the relationship between the SCN2A phenotype and the impact of the mutation on brain cell function.
Ms Kris Pierce RN MHSc MWellness, is a rare disease advocate and mother to Will who has SCN2A. Kris has held a range of board, project management, advocate and consumer representative roles and has been instrumental in working with local, state and federal governments to secure funding for multi-million dollar projects. Kris is highly skilled in building teams to work together collaboratively and is a co-founder of Genetic Epilepsy Team Australia (GETA) and SCN2A Australia, and a RARE Global Advocacy Leadership Council member.
Intro: Welcome to SCN2A Insights bringing you the latest research and clinical updates on SCN2A and genetic epilepsy from around the world.
David Cunnington: Hi, I’m David Cunnington.
Kris Pierce: And I’m Kris Pierce.
David Cunnington: And welcome to another episode SCN2A Insights. Our aim is to try and give people a better understanding of what’s going on in the SCN2A community. In this episode, we are going to focus on the natural history study that is being coordinated by Dr. Katherine Howell, our guest. Katherine is a pediatric neurologist and epileptologist at the Royal Children’s Hospital in Melbourne and she had done a lot of work on SCN2A-related disorders including a key publication that outlined the clinical presentations of SCN2A.
Kris: Pierce: So welcome, Katherine.
Katherine Howell: Thank you, Kris.
Kris: Pierce: Today, we are going to talk about natural history study and why it’s important within the rare disease space. So can you explain to us what is a natural history study?
Katherine Howell: A natural history study looks at the evolution of a condition over time. In the context of SCN2A-related disorders, that sometimes means from before the child is born and then up until the current age and ideally beyond. And the reason for doing a natural history study is we need to have a good sense of how a condition evolves over time for a couple of reasons.
One is to be able to inform families about prognosis and what to expect for the future and inform our clinical care, but the second and really critical reason is that it will help inform future treatment trials. When we do future treatment trials, we need to decide on particular outcome measures and how would we know that a treatment has improved a child’s condition over and above what would be expected without treatment. And in order to do that, we need to know what you would expect without this new treatment.
Now, SCN2A is I guess a little bit different to some other conditions in that the type of symptoms you can have and how severe your symptoms are is somewhat variable. And we are hoping to tease all of that out with the natural history study.
David Cunnington: So thanks for that understanding about the natural history study. Who is actually involved?
Katherine Howell: The natural history study is being by led me at the Institute, the Murdoch Children’s Research Institute in Melbourne. A major co-investigator is Dr. Marcus Wolff in Berlin, in Germany. Marcus is also a pediatric neurologist with an interest in genetic epilepsies in general and SCN2A in particular. And Marcus was the lead author on the largest study of SCN2A-related conditions that was published in the journal, Brain, in 2017. So between the two of us, we have quite a lot of experience with SCN2A. We have involvement of some other clinicians around the world from the point of view of helping set up the study and helping us to recruit patients but we are the two major scientists at this point.
I also have a research team with a couple of research assistants who some of the participants in this study will meet along the way.
Kris: Pierce: So what does it look like for a family of a person with SCN2A, what does it look like for them to participate in this natural history study?
Katherine Howell: As part of the natural history study, we need to collect information about the participants. The information we are collecting includes, is there a SCN2A variant and a lot of information about their medical and developmental history with a real focus on how things have changed over time. For example, at what ages are certain development skills acquired.
The medical history aspects of it include details or features such as epilepsy, movement disorders, abnormalities of tone, gastrointestinal symptoms. So we are really covering a real broad brush of things and not just focusing on epilepsy or just focusing on intellectual disability for example.
In terms of what is actually involved, we collect information from the parent or the participant themselves, in most instances, likely the parent, and also obtain medical records. So the parental questionnaire is actually part a writtenquestionnaire and part an in-person or over-the-phone interview for most participants unless they happen to be in Melbourne.
Then the medical records we will obtain include details of the medical history but also we would like to obtain the EEG recordings and the MRI brain images where children have had a brain scan as well.
The participants in Melbourne or probably in Berlin as well, we would also have an in-person assessment. We would love to be able to do this for all participants around the world but it’s obviously very logistically challenging and so that won’t be part of the study for the other participants at this point.
We will be doing a baseline assessment. This is for the parental questionnaire and medical records collection which includes obtaining information for the whole of the child’s life up until the current point. And then we will be doing some yearly follow-ups to see what has happened over the previous year.
Kris: Pierce: And you mentioned when you are talking then about people participating around the globe and that this is actually an international study, how do people get involved? How do they become part of this natural history study?
Katherine Howell: So if people are interested in participating, they can email us. The email address is SCN2A@mcri.edu.au.
Kris: Pierce: So you said Marcus Wolff is going to be doing some patients with SCN2A through Berlin. Do all of the patients come in by you and then you will forward them on to him?
Katherine Howell: Largely at this point, yes. So unless that participant is already known to Marcus in which case, he will likely arrange that directly. At this point, we will get everybody to contact us via the email address and we will take things from there. The process from there is that we will send out some information for the participant or parents to read. We will be available to answer any questions about participation and what the study involves. If the family is keen to participate then we will confirm their child makes our study’s eligibility criteria and then get written informed consent from the study and we will take it from there.
David Cunnington: So it sounds like there are lots of questionnaires. What if English isn’t someone’s first language or German for that matter?
Katherine Howell: We certainly recognized that’s a really major logistical issue that could limit participation and unfortunately, like many Australians, I and my research team only speak English so we are not particularly helpful on that front. We are very lucky that Marcus in involved. He speaks German, French, and some Spanish. So at this point, the plan is that we in Melbourne will study all English-speaking participants. He will conduct the study on German, French, and possibly Spanish-speaking participants. We would love to be able to include people who don’t speak those languages. We just need to work out the logistics of those. We would love people to still get in touch with us if they don’t speak one of those languages. We hope that we will be able to work something out that might include arranging an interpreter.
Kris: Pierce: So people around the world no matter what language they speak should express interest in the study if they are interested in participating and just highlight what language they would need to participate if it’s not English.
Katherine Howell: Absolutely. And we will do our best to find someone who can help us there.
Kris: Pierce: When you are talking about the process of becoming involved, you are talked about IRB approval. What is that and how can patients or families who are involved in this study be assured that their data is being securely managed under the ethics guidance of the institution which it has been approved?
Katherine Howell: This is a really important question and something we take very seriously. IRB is Institution of Review Board. That’s the name by which it’s commonly known in the US and some other countries. In Australia, we called it our Human Research and Ethics Committee. But basically, it’s referring to the ethical oversight of the study, approval by the institute of the study, and how do we guarantee we will conduct ourselves ethically, protect people’s privacy and protect people’s information.
Now, there are very strict guidelines and criteria in Australia about how we do that. We have ethics approval at our institute, at the Murdoch Children’s Research Institute. Marcus Wolff has his own IRB-approval through his center in Berlin. Our ethics approval allows us to recruit anyone from anywhere around the world from the point of view of studying participants and what we do with the data. I am the lead investigator and I’m responsible for the conduct of the study and the data. The data is owned by me and my institute. Identifiable data will not be shared outside our institute and outside our research study unless we have the express permission of the participants.
We do have approval to share de-identified data, meaning no names, no dates of birth, those kind of identifiable information with our research collaborators for other work on SCN2A and related epilepsies and brain disorders. But we are very careful about the data that we share.
Kris: Pierce: Should another researcher or an industry partner want to access that information, is that possible for them to do that if they are developing a treatment or a research project within SCN2A?
Katherine Howell: There’s not one single answer to that question. Maybe let me take it a couple of parts at a time. One thing I didn’t mention in my previous answer is that our study is supported by the Simons Foundation. Now, you probably know the Simons Foundation well, a large US-based organization that is conducting research into various genetic conditions, largely originally based around autism but expanding to other neurodevelopmental things. And a reasonably large SCN2A cohort. We have an agreement with them that they have helped us advertise the study and have shared with data with us, which is fantastic and we are very grateful for the support. As a reciprocal thing, we have agreed to share our data back with the Simons Foundation if the participant agrees to that. We will not share any data without the participant’s approval but we do have that existing arrangement. As far as other researches go, we will sometimes share de-identified data but that’s not a blanket yes. We need to I guess take each request on its merit. We need to evaluate who is requesting it, what are they planning to use it for, would we be following the guidelines of our ethics committees and also do we think that the sharing and use of the data will actually benefit science and we need to be convinced of the rigor and the importance of answering the question that the researchers are trying to answer.
David Cunnington: Thanks for giving us an idea about the study. How is the study going?
Katherine Howell: It’s going really well. So we launched the study earlier in the year and things were a little slow until we got research assistants on board a couple of months ago which we now have and they are fantastic and they have really accelerated the process. We have over 70 expressions of interests so far. We are sort of working through obtaining consent and studying all those participants but we have studied a number of them actually in a number of different countries around the world.
So, so far, I have some parental questionnaires with people in Australia, the US, England, Ireland, Spain, Germany, and soon to include Italy. So that’s wonderful that we’ve had interest from a number of places around the world.
David Cunnington: Yeah. And certainly from our own experience, we really learned a lot with going through those questionnaires with you. It forced us to stretch our memories about what had happened some years ago with our son. Thinking about how our son’s symptoms may have changed and evolved over time. That’s a helpful process for us too.
Katherine Howell: I’m glad to hear that.
David Cunnington: This is really exciting. It sounds like you really are making great progress. But how long has this been in the works? It sounds like it takes a while to get up and get going.
Katherine Howell: Absolutely does. It takes a long time. So we really launched the study in early 2019 but this has been in active preparation I guess since the second half of 2017 so it’s sort of a good 18 months to 2 years getting it together up and running. Things like getting IRB approval takes a long time. Things like planning questions you’re going to ask and the things you’re going to analyze takes a long time. Getting databases set up, employing people all takes a long time. And then the really critical thing is that we need to obtain funding. And we were lucky enough to be able to obtain that to do the study. One of the things that’s always difficult in scientific research is we’ve got more ideas than we have funding to do. So that’s a real stopping point. But luckily for us, we are up and running and it’s fantastic.
David Cunnington: Congratulations on the work you’ve done so far, both in getting it up and running but now really getting things moving along and starting to collect the information that as a community we really need to help drive treatments.
Katherine Howell: Thanks, Kris and David, for having me on your podcast today. I just want to say a really big thank you to you and all of the other families who have given so generously of their time to be involved in this study. I really appreciate it. Thanks.
David Cunnington: It’s great to hear from Katherine about what’s involved in the international natural history study. Personally, we can say having been through that process with our son, we found that it did take a little bit of time going through all the questions but actually really enlightening and we learnt some things reflecting on his experience and our experience in managing him with SCN2A.
Kris: Pierce: If you are interested in more information on the international natural history study, we will put all the information in the show notes for this episode. Keep up to date with the latest updates by subscribing to this podcast.
David Cunnington: Or get regular updates on SCN2A through SCN2A Australia’s Facebook or Twitter @SCN2AAustralia.
Outro: This podcast is not intended as a substitute for your own independent health professional’s advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider within your country or place of residency with any questions you may have regarding a medical condition.