Transcript
Fabio:
Hi everyone and welcome to this interview with Michaela Scharpe. Michaela is an expert in non-clinical development for cell and gene therapy products, having worked in both Biotech and large pharma and having designed and implemented many non-clinical development programs for cell therapies, induced pluripotent stem cells, somatic cells, gene therapies and… tissue engineered products. So, welcome Michaela to this interview.
Michaela Sharpe:
Thank you.
Fabio:
And thank you for being here. So I’d like to start with this very interesting and basic question. So a number of products, a number of cell and gene therapy products have been approved. And how have non-clinical development programs evolved during this past 10, 15 years? Have regulatory expectations changed?
Michaela Sharpe:
So I think. The basics of non-clinical development remain the same. So a non-clinical programme is there to define the potential efficacy of a product, to help identify the clinical dose and dosing strategies, and also to determine efficacy. And that principle hasn’t changed. But with some of these advanced therapies, actually how you achieve those goals does differ and I think fundamentally where that change has occurred and perhaps more clarification of those issues, it’s around the science of the product. So what is your therapy? How are you planning on targeting the disease? What are the particular aspects of the disease? And perhaps how you’re engineering that therapy. And so the safety and efficacy characteristics are really driven by the science of the therapy. And from a regulatory perspective, this means that… perhaps over the last few years, there’s been a clearer indication that the risk-based approach to individualised design of programmes is the norm. They expect you to look at the science, work out where the risks are and what are the most appropriate studies to actually determine those end goals. There’s no set of studies, as you would have for traditional therapies, but very much a science-driven, data-based approach.
Fabio:
Thank you. Thank you for that. And so given the novel nature of these products, for many of them we talk about living cells, is there a role for non-animal testing methods?
Michaela Sharpe:
I guess the short answer to that is yes. And absolutely there definitely is. But obviously expanding on that. So there’s over the last few years there’s been a real rise in the number and types of in vitro or ex vivo and even in silico methods that are being developed and certainly for some of these therapies, these may be really important technologies that potentially can be used. And this is something that’s recognised by the regulatory agencies. So across the world, agencies are changing their guidance for the use of non-animal testing. And even actually in the US, the FDA are actually changing the legislation. All to say that, you know, where it’s appropriate, non-animal testing methods can be used to support the clinical translation of therapies, not just cell therapies, across the board. And there’s clear evidence of that appearing in the cell-based therapies. So a very good example is teratoma testing. So for pluripotent stem cell undifferentiated cells. And in the past, this has meant large, long studies in immune-compromised animals lasting up to six months looking for the formation of teratomas. And now there are methodologies employing things like qPCR, which can very rapidly look for the presence of rare individualized cells. And so this not only achieves the obligations of the 3Rs but also is much cheaper and much quicker, and probably more accurate as well. The sensitivity of the assays are considerably greater. So that’s just one example. And with immune therapies where actually animal testing has questions of relevance in a lot of aspects to do with efficacy, there’s a really strong set of data out there for a number of products where they have used in vitro-based approaches, which are much more relevant using human cells human targets, so definitely a role for non-animal testing methods.
Fabio:
Thank you for that. And now maybe building on that, so given the novel nature of these products and the rare conditions that some of these products are going to treat, are there ways in which these non-clinical, like these pre-clinical programs might unexpectedly support the final marketing approval of this product?
Michaela Sharpe:
I think this is a really good question. I think it’s a really important point that a number of these products, particularly in the gene therapy space, are for rare and ultra-rare diseases, but also in cell therapy space you may have only short-term data in your clinical populations. And this is where actually early in development if you think about your animal models and where you have a really appropriate animal model of disease, there is actually the potential to generate long-term efficacy and safety data and this may ultimately be able to supplement your clinical package which may be quite small or limited in duration and this can be very valuable in discussions particularly with reimbursement bodies where they’re going to be considering you know the potential longevity of the response that you’re seeing. So just as a very brief example recently it’s been reported for studies in dogs with haemophilia which have been treated with an AAV gene therapy. Data has now been presented for up to 10 years on the longevity of the response, good safety data, so this is really supporting the potential of that therapy group for a long-term response in those type of diseases and so that’s really supportive data. So I think when you’re starting on a type of ultra rare disease, do think early that your preclinical data could be part of your support data package because obviously you want to have the time to do those studies but it really is something that people should consider perhaps early on in the sort of development of it’s not always feasible but where it is feasible it can be very powerful.
Fabio:
Yeah, it usually helps having a long-term vision even at a very early stage.
Michaela Sharpe:
Absolutely.
Fabio:
Well, I’m glad to hear that. So from now, and I’m sure you’ve been in this situation many times, so we’re now again, let’s assume you’re talking to a scientist, a scientist who has novel research, whether it’s cell or gene therapy, and they want to progress this research into a new product, cell therapy product, what would be your three key tips to put them on the right track from a pre-clinical development perspective?
Michaela Sharpe:
I think first and foremost… think about your animal models or your, I guess not even animal models, as we’ve just said, the models that you might be using, particularly to consider your efficacy and your safety. Really think about what is out there, what is available, what it can tell you, what it can’t tell you and have a really good view as to why you’re choosing a given set of models. Sometimes it’s very easy to fall into a trap of just doing because this is what everybody’s done, appropriate and I say particularly with these new novel in vitro models coming along. So really think about what you’re using and why because it can really help to accelerate your program because you choose the right models for the right studies and also don’t assume that a regulator wants a specific thing. Often people will say to me regulators want specific studies. What regulators want is the studies that address the scientific questions and the that you’ve identified. So really that time upfront spent planning what you intend to do and also because that allows you to get maximum information out of a study which is obviously very efficient particularly has the ability to allow you to maximise what you get from a study but also to move to clinic and through that clinical pre-clinical phase faster. One of the other things to think about is your product. In the ideal world, you will have your final product when you start your preclinical programme, but you won’t. And so understanding how that product will change and how your early studies can support your preclinical development programme, so you don’t have to repeat too much. So understanding what the differences mean as they occur and what is the impact on the data that you already have. So that also means you need to be working with your CMC colleagues so that you understand because what you don’t want them to be doing is to make a change and you have no idea that change has been made. But also to understand that changes will occur. Everyone tells you they don’t want changes, but they will occur and it’s how you handle it. So the other thing is to make sure you keep as much information about the products that you use for a specific study. The best to your knowledge at the time, it will improve as you go along, and help you utilise that early data that you have that can be really, really valuable. And I think the third point is engage with the regulators. There are various… meeting types that you can have very early engagement. The UK, the US, Europe, actually across the world there are various mechanisms that allow you to have that early engagement and with these novel programmes when you’ve got a non-clinical programme that itself is novel, have that early engagement because if the regulators have a specific concern or specific issue they want you to address you want to know about it early, you don’t want to be finding out So really make use of those meetings because they’re really valuable and really very, very helpful.
Fabio:
Excellent. Thank you, Michela. It’s been great to have you here and I’ve learned a lot and I’m looking forward to learning even more during our workshop and with this, thank you one more time and until our workshop. Bye bye.
Michaela Sharpe:
Thank you, bye.
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