Interviewee: Anthony Lodge
Interviewer: Fabio D’Agostino
1. What is the role of Regulatory Affairs in drug development?
2. You are talking to a scientist who is about to set up a company to turn his/her research into new cell therapy products. He/She is developing a plan to IND and clinical trial along with an interested investor. What would be your 3 key tips to set them on the right track from a regulatory point of view?
3. We often hear that potency assays and comparability studies are key challenges for cell therapy product. What in your opinion are the key CMC-Regulatory hurdles for ATMPs?
4. You have worked on many cell therapy products (pre- and post-approval), Do you think some regulatory challenges are cell type specific? Would you say that a stem cell based product is more complex to develop than a CAR-T from a regulatory point of view? Is there a correlation with the cell type, source, therapeutic indication?
Transcript
Fabio:
Hi Everyone and welcome to this short interview with Anthony Lodge. Anthony was a key contributor to the EU regulatory affairs strategy for Kite pharma, CAR-T products, Yescarta and Tecartus. And he also had experience with stem cell based products, having worked at GSK and Chiesi. He’s now senior director of regulatory affairs, T-Knife Therapeutics. Anthony, welcome.
Anthony Lodge:
Good morning,
Fabio:
Anthony.
Anthony Lodge:
Thank you for giving me the opportunity to speak to you this morning.
Fabio:
It’s a pleasure. So I was really looking forward to our interview. I’d like to make this as useful as possible to our abroad audience. So can you start by telling us what’s the role of regulatory affairs in drug development?
Anthony Lodge:
Yeah, thank you Fabio. Regulatory affairs is actually quite a broad discipline. The essential role of regulatory affairs is to be the interface between a biotechnology company and the regulatory agencies who will approve the drugs that the biotechnology company is developing for use in either clinical trials or for marketing application. So I think that that’s the key role of regulatory affairs but within that there’s various different types of work that we do to make that happen. There’s two sides as well, really, two regulatory affairs. There’s the clinical side. So that’s the side of regulatory affairs who looks after the clinical trials initially. Also typically looks after some of the applications to get regulatory designations that can support development programs, such as orphan drug designations, such as prime designations, such as breakthrough therapy designations. And then, the clinical regulatory team will also support the clinical development team to put together clinical protocols that the regulatory agencies can approve to ensure that a clinical trial will go forward. The other part of regulatory affairs is CMC regulatory affairs, and that’s the role that I do. So CMC regulatory affairs is all about supporting the manufacturing of a medicinal product. So within a biotechnology company, there’s usually an organization called technical operations. The name differs between companies, but technical operations is a good general term, I think. So technical operations encompasses everything that’s focused on developing a manufacturing process, quality control procedures, etc. for a medicinal product. So you’ve got the process development people, you’ve got the analytical development people, you’ve got the quality control people, you’ve got the supply chain, you’ve got manufacturing. So my role is to work with technical operations to develop a CMC strategy that will fulfill in a technical dossier, so module 3 or an IMPD, that goes to the regulators for them to review how the product is made and for us to demonstrate to the agencies that the process is well controlled and is delivering a product of suitable quality that’s also safe and efficacious to be used in patients in a clinical trial and ultimately in commercial use through marketing applications. So you know there’s a lot involved in putting together that CMC strategy that aligns with the regulatory requirements presented in the regulatory dossier. Discussing the plan with the agencies through scientific advice type procedures for example. So really they’re the two key disciplines of regulatory affairs, CMC regulatory affairs being my particular role.
Fabio:
Thank you. So now let’s imagine that you are talking to a scientist who would like to set up a company to turn their research into new medicinal products, new cell therapy products. And they are trying to develop a regulatory affairs strategy, like a development strategy to IND, possibly with an interested investor. What would be your key three tips to set them to the right path from a regulatory point of view? Because I understand that setting up a company is a very complex task, but from a regulatory point of view..
Anthony Lodge:
Okay, there are probably more than three.
Fabio:
Yeah, I see
Anthony Lodge:
But let me choose three for now. So I think the first one would be to… hire people who’ve got really good experience in the industry and in regulatory affairs. I think to put together a good regulatory strategy and effective regulatory submissions, then it’s really important to have experienced people to do that. I think for small startup companies, they’ve got the opportunity to use consultants. There’s lots of consultants out there who are probably a good first start while a company is getting set up but I think it’s really key to hire people either as consultants or you know as full-time employees who’ve entered high level positions who’ve got good experience that can execute on a regulatory strategy. That was number one. Number two I think it’s important to understand regulatory frameworks. That is obviously mainly the role of the regulatory affairs professionals, supporting the development program, but I think also for an organization as well, more broadly, it is good to understand regulatory frameworks in US and Europe in particular. You know, not to the level, I guess, of the legal framework and directives and regulations, but you know, what the agencies do is they develop guidance documents that delineate the expectations of what development program should incorporate. So I think it’s really important to understand that the regulatory frameworks, you know, be aware of the guidelines out there and use them to inform the strategy for your particular development program. Okay, so my third tip and building on that knowledge of the regulatory frameworks would be to actually interact with the regulatory agencies. So the European agencies through scientific advice meetings or the FDA through meetings such as pre-IND or interact meetings. I think it’s really important to talk to the regulators certainly in, you know, early stages of development, pre-phase one for example, to ensure that the way that a development program, the strategy for a development program is designed is going to fulfil the regulatory expectations. So obviously there’s the knowledge that comes from understanding the regulatory framework and the guidelines but… actually seeking that direct feedback from the agency is really important. So engaging in scientific advice is a key tip
Fabio:
Okay, thank you. So then, we often talk about… potency assays and comparability and it seems that they are the biggest hurdles in ATMP developments but I would like to ask you what do you think are the most difficult, like the biggest challenges when it comes to CMC regulatory affairs for ATMPs in particular?
Anthony Lodge:
Okay, I think there are many CMC regulatory challenges with ATMPs. They’re probably product specific as well, but comparability studies and potency assays are very important things to talk about. Let’s think about why they are needed. So potency assays are needed to demonstrate that an ATMP will have… biological activity and we can therefore predict that it will be active in patients once they are treated with it. So a potency assay is a key aspect of the release testing for a product. But you know it takes time, it takes work to actually develop potency assays. Certainly in the beginning of a development programme there will probably be multiple potential potency assays that are under development until one can be selected based on being the most robust reader but also correlating with efficacy in patients. And you know it’s not until patients have been treated until you can actually correlate that release test that the data from a potency assay with the clinical data. So that’s the challenge in early development. But, you know, certainly for a lot of the T cell therapies, CAR T cell therapies now, then interferon gamma expression is commonly used as a potency assay. And even if it’s not perfect at phase one, then at least something can be implemented. And I think it’s important to be collecting data on biological activity, even if it’s not assigned as a potency assay, you know, from phase one. So, you know, implement potency assays or potential potency assays as early as possible, because it’s important to correlate that activity with the clinical response so you can understand how the product is working. But you also asked about comparability studies. Comparability studies are important because manufacturing processes for ATMPs in particular are most likely to evolve during the development programme, so most organizations will want to implement a few changes, improvements to the process, maybe they want to change the way in which the cells are enriched from the starting material, they may want to change the actual culture conditions or use different materials, for example, just make various improvements just to improve the process, which is, you know, natural evolution of process development. So comparability studies are really important to show that when those changes are made, after patients have been treated with, the quality of the product is not changed, certainly not impacted negatively from those changes. So that’s the point of doing comparability studies so that you can compare different flavors of the product from different versions of the process that have been used in patients during the various phases of the clinical studies. Potency assays are a key part of that because it allows you to demonstrate that the product continues to exhibit biological activity. So the two things go together. I think because changes are going to be made throughout development, you need a robust analytical toolkit, shall we call it, to be able to assess how those changes impact product and potency is a key aspect of that. So the two things definitely go together. I think another thing that many startup organizations probably need to be aware of from comparability studies is that the design of those studies, you know, can be quite complex and needs to be set up appropriately to be able to generate data that can meaningfully conclude on the impact of particular changes. And that’s where it’s important, going back to what we were talking about earlier, talking to the regulatory agencies seeking feedback and scientific advice meetings on the design of comparability studies, for example, to make sure that the design is correct, the statistical approach to analyzing the data correct, but also the analytical toolkit is correct to be able to generate meaningful data on process changes that are being made.
Fabio:
Yeah, because we need to generate the right data, quality is more important than just quantity
Anthony Lodge:
Mm-hmm.
Fabio:
I guess. So you would agree that potential comparability are, let’s say, among the biggest challenge, the biggest hurdles when it comes to CMC regulatory strategy for ATMPs.
Anthony Lodge:
Yeah, absolutely. Simply because, you know, you need to be able to show the impact of changes on your manufacturing process, on the quality of the product, and the quality of the product is intricately linked to its potency.
Fabio:
Well, thank you. And now I’m thinking back to what we were saying at the beginning, that you work both on pre-approval and post-approval, but you worked with T-cell-based products, Yescarta, Tecartus, but also with stem cell-based products like Strimvelis, product is more difficult than developing a T-based cell therapy? Is there any kind of correlation with cell source, cell type, even therapeutic indication from a regulatory point of view?
Anthony Lodge:
It’s a good question Fabio and I think the answer is that one type of product is not necessarily more difficult to develop than another. Maybe if I was to explain why certain products may be more difficult to develop than others it would be in the case of genetically modified cell therapies compared to cell therapies which are not genetically modified. And that’s simply because you need to also modify the cells as well as expanding the cells too. So usually for genetically modified cells, they are modified with, they’re engineered with viral vectors. There are now non-viral vector approaches that are under development as well and becoming more prominent but there’s a mechanism for genetically modifying cells as well. And with a vector, then you have to manufacture a vector as well. And the amount of development work, CMC development work, that’s involved in developing a vector is really the same as developing the cell therapy itself. So in many ways, you’re developing two products in one. But I think I wouldn’t… necessarily try and argue that a stem cell therapy is more difficult to develop than T cell therapy or vice versa because each product has its own product specific challenges and that need to be understood. All cell-based therapies begin with a starting material from which cells are enriched and then those cells are usually expanded in culture, they may be genetically modified etc. The important thing about any cell-based therapy is to understand what product you want at the end. So starting with a mixed population of cells in the starting material, in the tissue of interest, you need to get a particular cell population at the end that mediates the pharmacological activity. So you need to understand how… to design a process to go from starting material to the finished product. But then understand as well how the process is impacting the cell population that you’re working with. Impurities that are there in the starting material at the beginning, how they may persist in the product, even if you’re enriching for a particular cell type process changes may impact, you know, those different populations of cells in the starting material. So the hard work is about characterizing each particular product and designing a process that will deliver the right cell type that you want with the desired pharmacological activity.
Fabio:
Thank you, thank you Anthony. I learned a lot and I’m certainly very pleased to see where we are now as an industry compared to where we were like eight to 10 years when let’s say, we’ve seen the first CAR-T product approved and the first kind of stem cell based product approved. So thank you so much for your insights today, I learned a lot but I’m looking forward our workshop and until then bye
Anthony Lodge:
It was great to speak to you. Thank you, Fabio.
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