Common pitfalls to avoid when planning a marketing application for cell and gene therapies

Developing a successful marketing application involves several strategic steps, as described by Kevin Hennegan, Senior Regulatory Strategist for Veristat. Listen as Kevin identifies some of the key components of a cell & gene therapy marketing application in the US and EU, and outlines several of the most common pitfalls and gaps that he has encountered with sponsor applications. Listen now. 

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: 0:24

Hello, and welcome to the art podcast. Advancing revolutionary therapies, a podcast presented by the center of excellence for cell and gene therapies at Verad. My name is Kevin Henn, senior regulatory strategist. With Verad today, I will be presenting common pitfalls to avoid when planning a mark marketing application or biologic license application for your cell or gene therapy product. This is part of a series of podcasts discussing various topics pertaining to the development of cell and gene therapy programs. And I encourage you to listen to some of the previous episodes. If you haven't already, the objectives of today's podcast are to identify some of the key components of a cell and gene therapy marketing application, and to outline some of the most common pitfalls or gaps we've encountered with sponsors applications, I will be focusing on us biologics license applications, but many of the same principles apply for marketing applications in the EU and UK. I will address some issues that are unique to cell and gene therapy products, but many of the application components and pitfalls are common to novel products regardless of product class. One of the first mistakes that we see sponsors make is neglecting the importance of a pre-application meeting with the applicable health authority. For example, the pre B meeting with FDA, these meetings are an opportunity to discuss in fine detail the data the, that will be included in your marketing application. This process helps to orient the authorities review team to your application and provides an opportunity to negotiate agreement on some of the more complex areas of product development. If there are any issues or requests from FDA that were raised earlier in the development program, this meeting is a good time to ensure those have been fully resolved. It is important to strategically plan the timing of these meetings. Ideally, you'll want to target a point where top line data from the pivotal clinical studies are available for the briefing package, but with plenty of post-meeting lead time prior to the target submission date at the licensing application, this will allow a meaningful discussion with the agency and allow time to address an any issues raised and continued discussions. If necessary. One important topic to cover during pre-application meetings is the selection and validation of potency assays. This topic is not unique to selling gene therapy products, but certainly can be more challenging in this product class than in others. Ideally, potency assays should reflect a product's mechanism of action. Many S cell gene therapy products have complex or in completely characterized MOAs. Consequently S gene therapy products may need more than one potency assay as part of their release testing package. It is certainly worthwhile to discuss the selection and validation parameters for these assays in an effort to obtain buy-in from FDA prior to submitting a Bela continuing on with CMC topics, we should talk about requirements for process validation, as they pertain to cell and gene therapies. Many of the principles of process validation that apply to other classes of therapeutic carry over directly to cell gene therapies. However, there is some inherent manufacturing variability associated with these products, particularly for auto autologous therapies and your process validation plan should account for that while still demonstrating the capability of the process to result in a consistent product that meets your established for purity, potency and safety process validation for cell gene therapy products will usually also include an aseptic processing validation exercise. The use of media fills to demonstrate the ability of your facility to prevent microbial contamination is well established, however, demonstrating full sterility assurance for cell therapy. These can be challenging, particularly if the product has a short shelf life, you may need to implement a combination of rapid testing methods, such as PCR or direct microscopic examination with post-release evaluation of standard Pharmacal durability methods. In order to satisfy regulatory authorities to close out our discussion of CMC topics for today, I wanted to address facility inspections. If the manufacturing facility has not been previously inspected, you should expect to host an inspection by FDA or other health authority sometime during review of your marketing application. This remains true even during the current COVID 19 emergency. As these preapproval inspections are usually classified as mission critical activities by FDA that said the pandemic is a dynamic emergency. So you should consult with your FDA project manager and the FDA website for the latest information. It is possible that the pandemic could delay inspection of your facility. For example, if regional travel restrictions are imposed, which could delay the overall review timeline of your application. Also note that health authorities may ask that the inspection be scheduled at a time when they can observe active manufacturing operations. This can be challenging for small throughput and or on demand manufacturer of cell and gene therapy products. So it is a good idea to start planning early, for ways to accommodate such requests. As one example, a manufacturer of an autologous cell therapy. I worked with established a tissue collection, only clinical protocol, which allowed them to collect cellular material for initiation of manufacturing runs dedicated solely to process validation and inspection activities. Nonclinical studies such as animal toxicology programs challenging for cell and gene therapy programs, but inves stat's experience. These are usually well resolved by the time a program is ready for a marketing application. So I'd like to press straight on to clinical topics. One such topic that we have seen trip sponsors up at the marketing application stage is the absence of a study data standardization plan, or S D S P the SD S P is something that should be put in place and discussed with regulatory authorities early in development. As this plan supports harmonization of data to enable meta analyses across multiple clinical studies, such a as your integrated summaries of safety and efficacy in the absence of an SD S P the time required to prepare ISS and ISEs that are acceptable to health authorities may increase significantly sticking with clinical statistical documents. Let's move on to the topic of reviewers guides. These guides should describe any special considerate directions or conformance issues that may facilitate a health authority. Reviewer's use of the submitted data and may help the reviewer, understand the relationships between study reports and the data. They are an important, but sometimes neglected component of study data submissions. As they consolidate information from multiple documents into a single source that will orient reviewers to the analysis data sets a clinical topic that may seem obvious, but is absolutely critical to a successful marketing application is the selection of clinical efficacy endpoints, depending on your target indication, there may be well established precedence for outcome measures that are acceptable to health authorities, but many cell and gene therapy products, target rares diseases where precedents may not exist or are much less clear. The key relevant factors associated with endpoint selection are connection to your products. Mechanism of action, the intrinsic variability of the endpoint in your target population and the clinical relevance of the measure. My colleague, Robin BLIS discusses these considerations and more in a separate episode of this podcast. And I encourage you to listen to that. If you have an interest in this topic to close out our discussion today, we should spend a moment on long term clinical follow and to postmarketing studies because many cell and gene therapy products are designed to be effectively. Permanent regulatory expectations for follow up are much more extensive than they are for more train applied therapies. You should expect to collect five, 10 or even 15 years of safety data on patients treated with your product depending on product class and indication collection of long term efficacy data may also be needed, particularly if the initial approval is based on data from a surrogate endpoint, your initial marketing application should to include plans for collecting and reporting these data. This topic is discussed in more detail in episodes presented by my colleagues, Rachel Smith and Mariana Oviedo. So I encourage you to give those a listen as well, to summarize our discussion today, here are the key points I've discussed. Be sure to use the free B meeting strategically to clear the path to your life application. Start working on development of potency assays for your product early in development, and attempt to obtain FDA buy-in on the design and validation of these assays prior to submitting your BLE build product appropriate flexibility into your process validation plan, plan on and prepare for FDA inspection of your facility, even during the COVID pandemic, but check the FDA website for the latest guidelines and announcements on what to expect, ensure that you talk to your CRO about preparation of study data standardization plans, reviewers guides select your clinical efficacy endpoints based on clinical relevance, outcome measure variability and your products. Mechanism of action. Get FDA buy-in on your choice prior to initiating pivotal clinical studies. If at all possible, finally include your plan for conducting long-term followup studies in your initial marketing application. These are, are just a few of the issues that can slow down or derail marketing applications for cell and gene therapy products. Veristat has extensive experience in this field and can help you develop a detailed strategic plan tailored to your product that will reduce your regulatory risk. I encourage you to continue listening to future episodes of this podcast and reach out through the links available on the Verta website or through cell and gene.expert. If you have questions or feedback, we will be back and talking to you again soon. Thank you for listening.

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