Long-Term Follow-Up Studies in Gene Therapy

Mariana Oviedo, Project Manager for Veristat, provides an overview of the key items that must be taken into consideration when designing and running a long-term follow-up study for a gene therapy product, sharing experiences from both a scientific and operational perspective. It is never too early to start thinking about the long-term follow up with so much on the line.

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 the podcast, advancing revolutionary therapies, both because presented by the center for excellence for cell and gene therapy by various stat. My name is Marianne Oviedo. I'm a project manager at various that working with our clients in cell and gene therapies. My role is to lead the planning, preparation and successful execution of clinical studies and activities that support our partners and their clinical research. And I'm delighted to come to you today to be discussing long-term followup studies in gene therapy. I highly recommend you check out the pockets episode developed by our medical affairs director on the safety aspect of gene therapy studies, which is a great compliment to the topics we will be discussing here today. So this, um, during this brief conversation, I will outline for you the key items that must be taken into consideration when designing and running a long-term follow-up study for a gene therapy product. I also want to share some of our experience from both the scientific and operational perspectives, and finally encourage all foreign source to start thinking as early as possible about their longterm followup studies and what they will look like before jumping into study design and study operations. I like to take a step back to ask why do we need these longterm followup studies? So the, the short answer is that, um, gene therapies are considered a long-term exposure to the investigational product. And therefore we need to have a clear picture of how they will impact a patient's life. Even after the initial exposure. Current guidelines on long-term followup studies were issued by the FDA in 2019, and they recommend 15 years of followup for wide range of factors, such as gamma retroviral, lentiviral purpose virus, um, microbial and transposon elements. And they recommend five years of followup for M and then no associated virus vectors or AAV vectors. Gender sign was the first, uh, gene therapy to be approved in China in 2003. And Glybera was approved in the EU in 2012. All these past clinical research and experience has contributed to determining the length of the long-term followup studies and understanding the risks associated with these gene therapy vectors. Many of the adverse events associated with gene therapies will occur even years after the exposure. Some of these adverse events include for instance, uh, some vectors usually retroviral vectors, or transposons delivering the genes to have the potential to integrate in the host genome and disrupt the activity of critical genes and, or activate proto-oncogenes and increase the risks of, eh, the risk of malignancies or cancer. Other gene therapy products have the capacity to edit the host genome and therefore the possibility that some, some of these edits can cause non desirable effects. Also gene therapy product that encode growth factors, um, may rise, uh, raise the risk of unregulated cell growth. And again, go back to increase in the cheese, eh, the chances of malignancies due to the prolonged exposure to the therapeutic protein and another potential risk is that when the, when the Victor is based on a herpes virus, there's always a potential for reactivation from latency and development of ag related to symptomatic infection. And last but not least, um, there's a potential for persistent infections that can be established when the gene therapy products are delivered by a viral or bacterial vector with the capacity to replicate immunocompromised. Patients are often at a higher risk of developing these delayed by bites, but serious infections. So depending on the, on the delivery system for them engineered genes, the, we need to consider, uh, some of these, um, potential adverse events. So, uh, the design offi, um, long-term follow, uh, follow up study should ideally begin along with the design of the parents study, where the patients will receive the gene therapy product. When designing a study, you want to keep a realistic perspective on and strike a good balance between collecting all the data. You need to meet your key objectives, but also not being, uh, an opposing too much of a burden on the sites and the patients and their families. If you, if you items to keep in mind when developing a study protocol are, are as follow number one in main objective for your study, it should always be to monitor long-term safety. Secondary objective is to monitor long-term efficacy. This is not required by the guidelines, but it is a nice to have for sponsors to better understand how their products affect our sustained in time. Sample size will always be a convenient sample as a patients that will meet the inclusion criteria will only be those that received the initial treatment in the parent's study and consented to participate in the long-term follow-up study. And lastly, the key end points to be collected will be heavily informed by the findings on the preclinical data on tissue accumulation, by a distribution profile potential for integration in specific areas of the genome, if any, as well as the findings from the parents study. So now I'm going to be shifting to talking a little bit about the operational considerations of running a long-term follow-up study. But before I jump into that, I just wanted to share some cool information that I learned while working on this developing this podcast episode. Did you know the various that land, the clinical study for the first gene therapy approved in Europe while preparing for this podcast? I had the opportunity to chat with several of my colleagues. Some of them worked on this first study and many of them who are currently working on longterm followup studies for gene therapies, um, all of them agree that the key to the success of these studies is maintaining strong, positive relationships with your patients, their families, and the sites from an operational perspective, keeping in mind factors that relate to study duration are key to the success of the study. So a few considerations to have in mind are the following number one, we need to adapt the study documentation to stand the test of time. One additional question we need to ask is will this document make sense to a PM or any other team member from say 10 years from now when probably all the original members of the, of the team are no longer in the company? Secondly, uh, similar rationale applies for different kinds of assessment being done for the study. For example, for one study, uh, we are using a specific, uh, promise assessment questionnaire, which is part of our EVC. After a couple of years, we realized that this questionnaire, my had changed considerably in time. So moving forward, we have made provisions to save copies of the version of the assessment that are being used. So that way, these can also be kept in mind while anytime that we need to update the CDC, the same rationale applies to certain laboratory tests that are being are being done for, um, for these patients. We need to know exactly what, uh, the protocols, uh, or how those tests are being done as well and how they are being, uh, the results are being interpreted. Number three, the major challenge for longterm followup studies is patient retention. As we mentioned before, the number of patients is pretty determined by the number of patients initially enrolled in the parents study. So we want to maximize the number of patients agreeing to participate in the long-term follow-up study and do our best so that they remain engaged while they years with the clinical study. And they are not lost to follow up. We recommend having a patient retention plan that can include newsletters for the patient, for the family postcards as reminders, whenever their follow-ups are coming. Another approach that has proven useful is to keeping the patient's main healthcare provider involved and copied in the followup process, even if they are not a formal site for the study. Lastly, one, um, just another mention, who quick mentioned to, um, basically the recent shift that we've had in, in acceptance and increase use of telemedicine as a consequence of the COVID-19 pandemic. This has reduced the, the burden on patients and their families, um, that can be followed up, uh, over the phone or over in a virtual visit. And as the COVID restrictions, uh, are relaxed, hopefully some of these tools will continue to be used. So to wrap up for today, it is important to keep in mind if you things monitoring safety is a key paramount of longterm followup studies, number two, keeping a good balance between collecting enough data to support your objectives, your study objectives, and not overburdening. Your site will be key to your study success. And number three, make sure that your study documentation can stand the test of time and team turnovers. I hope that you find these episode valuable, certainly reach out through the links available on the very start website for additional information. We will be back and talking to you again soon.

Speaker 1: 11:15

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