Common Pitfalls in Gene Therapy Studies

Rachel Smith, Portfolio Director for Veristat, takes us through a number of pitfalls to avoid when planning for a gene therapy study. With the stakes high and having conducted trials for the first gene therapy approved in Europe, put Rachel’s lessons learned to work when determining your regulatory pathway, logistics strategies and donor screening requirements.

Transcript

Speaker 1: 0:00

Bringing a cell or gene therapy to market is an art here. Vera stat thought leaders, as they draw on their specialized expertise to offer insight on timely relevant clinical development topics.

Speaker 2: 0:14

Welcome to art pop cost advancing revolutionary therapies podcast presented by the center for excellence for cell and gene therapies by barista. My name is Rachel Smith. I'm a portfolio director here at Ferris that working with our clients in cell and gene therapies, providing operational excellence from strategic consulting to clinical trials and post-marketing commitments today, I'll be discussing the common pitfalls to avoid when planning your gene therapy study. You may have already listened to the first podcast in this series presented by my excellent regulatory colleague, Kevin Hannigan on the common pitfalls to avoid when planning your cell therapy study. Not too late, there is some overlap between the two and if you haven't listened to Kevin's podcast yet, then I hired you to do so to gain a few of the nuances between these revolutionary therapies. The objective of today's podcast, let's discuss the definitions of gene therapy in the EU, in the U S and so outlined some of the most common hurdles we've identified for managing gene therapy programs. So how is the gene therapy defined in the EU? The EMA defines these therapies that contains genes that lead to a therapeutic prophylactic or diagnostic effect. They work by inserting recombinant genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases. The us definition is slightly different and defines this as a therapy that seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. Now that we've defined the product class, let's move on to the common pitfalls we at various staff seen for gene therapy programs. The first I'd like to discuss is the variability we see across international regulators whilst in the U S the landscape is fairly consistent with non gene therapy products, and that we need an active ind and IRB approval. We also need to obtain additional reviews at the IRB level, such as biosafety committees for this product type in other regions. It's not quite straightforward. For example, in Israel, the current ministry of health submission process does not actually accommodate these types of studies. And so we routinely have to go down a far more complex genetic study submission rate, which was actually originally designed for genomic trials to have a calmness, a close working relationship with regulators, particularly in less experienced regions is crucial and something the fire stat team is used to managing, even within the EU, the EMA have set out guidelines to harmonize advanced therapy trials. There are still regional variability. A key example is additional GMI approvals. So we need these approvals in place to be able to perform any genetically modified research within, um, within the EU. And it actually falls outside of clinical trial regulations. Each country has a different process and can even apply the definitions of contained use GMO versus deliberately released at GMO differently to the same product. And as you can imagine, that can significantly slow down startup timelines. Then thinking about the clinical trial directive itself, this sets out a fixed 90 day submission to approval timeline for advanced therapy trials. However, this can also be variable depending on the countries involved. So for example, in Italy minister to create allows for an additional hundred and 80 days, we requested by the competent authority IFA for specialist review of these trials. So it's not great if you're getting to the submission stage, expecting a 90 day Terminator turnaround and an additional six months is added to your timelines. It's vitally important to work with a team experience in navigating the regulatory landscape, and he can guide you with respect to country selection and timeline management. Next page four, I'd like to discuss his patient safety. Third gene therapy research has advanced significantly since the first gene therapy was approved in 2012. We asked to in the infancy, when it comes to understanding the long-term impact of these therapies on patient's safety, no doubt. If you are listening to this podcast, you will have seen the various gene therapy gone wrong headlines over the past few decades, designing a clinical program and patient safety at the forefront is critical. The ex vivo gene therapies, donor screening requirements must be considered. This is your requirement and key regions such to Europe in the U S to ensure the safety and quality of the starting material from your donor, regardless of whether your product is allogeneic or autologous, both the EMA and FDA published lists of infectious agents, that must be screened. And I encourage you to review these from repairing your clinical development plans, as they do differ, particularly if you intend to perform your clinical trials in both regions or market your product in both regions, in the feature other aspects, for sure and safety I, things that you must maybe familiar with from trials and other product classes, such as the inclusion of sentence in groups, dose escalation in early phase studies and the use of data or safety monitoring committees, as well as ensuring you have clearly defined stopping roles within your study protocol. A high rigor of safety monitoring is also needed. Some of the safety monitoring assessments important for gene therapy include immunogenicity studies, which look at antibodies against the trans gene, the core of your product, and may mean the development of new assays at the preclinical stage, which can add time and cost to your development program, monitoring Vata immune responses, particularly when it comes to selfish gene therapies. It's also important in addition and session site analysis should be performed. So either to ensure that the transgene in session does not favor onco genes, that's increasing the risk of post-treatment cancers, but also to monitor for off target events within the patient's genes. We also need to look at off target events in non unintended parts of the body. So either via genetic imaging or biological material studies, a great example of this was a recent gene therapy treatment for the eye with a viral based in therapy, actually migrated from the tree to die to the untreated eye there. In this case, the impact was beneficial. It highlights the potential risk. The use of replicant competent viral vectors is rare in gene therapy studies, however, replicant deficient vectors are favored, and there is still a risk that the viral vector maybe take into an RC vector. And so monitoring for this is critical. That's a shedding in viral based therapies may also need to be monitored to ensure that we're avoiding transmission of the transgene to untreated individuals though. The risk is actually significantly reduced when we're using replication deficient therapies, which form the majority of gene therapy, finally establishing monitoring methods for demonstrating persistence of your gene therapies of ultimate importance, particularly where your therapies aimed at lifelong persistence. For example, curative gene therapies for monogenic diseases like stem fellas for ADA skid moving onto the next pitfall traceability requirements there in theory, the traceability of a gene therapy product, similar to that, of any investigational drug in practice. This can be much more complex. For example, let's take an autologous ex-vivo gene therapy. Every single cell from cell collection to manufacturing to transplant needs to be tracked a robust vein to vein chain of custody process step-by-step documentation needs to be implemented. And the complexity is only increased a hundred fold when introducing multiple regions in global studies. So working with a team and a courier with experience in this setting is a must, as you can imagine, this is logistically challenging and leads me nicely into the penultimate pitfall logistics. The sheer nature of these studies throws up a multitude of logistical challenges for patient identification and recruitment site training, consistency of gene therapy, administration and patient follow-up. To name a few planning, your studies around like a practices in the patient journey is essential for success here at FareStart, we've created an adaptable toolkit for managing each unique aspects of gene therapy, trial logistics. For example, we created a central site model where patients to go screening cell harvest, if applicable and treatment unexperienced central site, I return home for either remote or local follow-up. Now follow up itself is one of the most common pitfalls. And this leads me to our final final piece. We touched on the unknowns around long-term safety and persistence of gene therapies, and it's usually a regulatory requirement to follow treated patients for anywhere between five and 15 years, depending on the type of gene therapy they regulate is all flexible and how this followup is managed. So whether we utilize a registry study, a formal long-term for that trial, or we even think about working with national network, such as the EBMT in Europe to monitor these patients, long-term what type of a design, including a plan for long-term followup in time for the first patient you roll over in your overall program is an absolute must. So the podcast today, it was really intended to be a high level overview of our experience. The most common issues that we see in these gene therapy programs, the take home message is essentially that lack of planning can cause significant delays with your development program. So addressing all these issues upfront in your clinical development plan will ensure success. And ultimately we'll get new therapies to patients faster, very that managed clinical trials for the first gene therapy to be approved in the Western world. And as trailblazers, we continue to be actively involved at the cutting edge of this field. We encourage you to listen to future episodes of this podcast. As we delve deeper into some of these issues and other important topics in satin gene therapy. I hope this has been valuable to you. Please reach out to our expert teams for the links available on the first site website. Should you have any questions and we'll be back talking to you very soon.

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