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CRISPR in the Clinic: Synthego’s Regulatory Experts Discuss Development of Cell and Gene Therapies

This blog post was written by Rebecca Roberts, PhD, et al. from Synthego, a genome engineering company that enables the acceleration of life science research and development in the pursuit of improved human health.

Taking a CRISPR therapy from the lab bench through to clinical trials is a long and arduous process, requiring extensive scientific expertise. However, it also requires expertise in an area that even the best scientists often find challenging - the regulatory space. As a leader in the gene editing industry, Synthego does more than simply provide GMP-grade sgRNAs, we also have unparalleled regulatory expertise, partnering with CRISPR therapy sponsors to help them along their clinical development journey.

Join us as we speak with Synthego’s regulatory expert, Lina Jamis, about what regulatory experts do, why the clinical development of CRISPR therapy products is so difficult and time-consuming, issues with preparing regulatory documentation and interacting with the FDA and other ways that Synthego can accelerate the path from bench to clinic. Finally, Lina shares her insight on recent regulatory trends and her predictions for the future of CRISPR therapies.

The Role of Regulatory Specialists and Challenges in CRISPR Clinical Development

If you’re not already familiar with the clinical development process and clinical trials, you might be wondering what a regulatory expert does and why they are so important. Here, Lina explains her work as a regulatory expert as well as the unique challenges of CRISPR cell and gene therapies (CGTs) in the context of the regulatory space.

Please tell us about your role(s) as a regulatory specialist for Synthego.

Lina: The role of regulatory affairs can be thought of as many things, but among them are two that stand out to me: 1) devising a regulatory strategy or framework for a particular product in development and 2) liaising between a therapeutic developer and the regulatory bodies that review those products.

What I find appealing about this role, particularly in the cell and gene space, is that regulatory frameworks for CGTs do not exist - there is not enough precedent for these products quite yet. This requires a certain level of innovation when it comes to regulatory strategy, which I think regulators like the FDA are open to.

Why is the clinical development of CRISPR-based therapies so challenging?

Lina: I think there is the challenge of a lack of precedence in the entire CGT industry - there are, of course, more and more CAR-Ts on the market, and many more cord blood products that have existed for longer, but the lack of precedence makes reviewing products with novel manufacturing schemes, novel mechanisms of action and assays to verify them, difficult.

Specifically for CRISPR therapeutics, there are no approved products on the market; the FDA is reviewing at least one of these products in the coming months (if not now), and the way that they deliberate on these products sets the tone for the rest of the CRISPR therapeutics that will inevitably come down the pipeline. The speed of development and the rate at which regulators have to review, regulate and also guide is part of the challenge in this space.

Regulatory Documentation: A Major Headache for Cell and Gene Therapy Sponsors

Two of the key hurdles that CRISPR therapy sponsors encounter during clinical development are broad regulatory guidelines and preparing the necessary documentation to submit to the FDA. Fortunately, Synthego’s regulatory specialists, including Lina, have a strong understanding of the FDA’s expectations as it relates to CRISPR products. Let’s explore these documents, why they’re important and how they apply to CRISPR therapies in particular.

Tell us about the common technical document (CTD) - what is it, and why is it important in the development of CRISPR therapies?

Lina: The CTD is a large dossier made up of several different modules that is required for all new drug products. It’s a way to standardize submissions to health regulators - the idea is likely that standardized review frameworks start with standardized submission processes and content. The CTD is important for all developmental therapies because it houses information regarding the chemistry, manufacture and control of the product, clinical data, historical data - it’s meant to include all of the data that a reviewer might need to fully judge the efficacy and safety of a therapeutic.

Because CRISPR products may be made up of many small gene-editing components, the CTD becomes the natural place to segregate these components and describe them fully in terms of their manufacture and control as this is a highly prioritized topic for health regulators.

What is a CMC module 3, and how can you help customers with it?

Lina: Module 3 (M3) is the section that houses all of the chemistry, manufacturing, and control (CMC) information for a drug substance and/or drug product. It includes information on the product’s manufacturing scheme, control of raw materials, processes, equipment and amongst other content, standards and safety measures in place to ensure that the resulting product is exactly what the developer claims it is.

Because an Investigational New Drug (IND) application is the first true opportunity for regulatory review of a product’s quality, it’s incredibly important that M3 contains accurate information as well as qualitative, non-superfluous detail on how these products are made. M3 is fairly standard, but writing this section for CRISPR products can be a challenge because of how these products are unique from your typical biologic: control of starting and raw materials, Good Manufacturing Practice (GMP) principles, informative analytical methods and characterization of the products and appropriate release criteria.

The Synthego Difference: Unparalleled CRISPR Expertise and Regulatory Support

For sponsors of CRISPR cell and gene therapies, choosing Synthego as your provider means more than simply securing a reliable supply chain of GMP-grade sgRNAs - we partner with you at every stage of the clinical development process to maximize your chances of success. In this section, we investigate the common areas of clinical development in which sponsors struggle, when is the right time to ask regulatory experts for help and the ways Synthego can increase the chances of novel CRISPR therapies being approved for clinical trials.

Where do customers seem to need the most assistance in the clinical development process?

Lina: Most clinical developers have really in-depth knowledge of one therapeutic type: it might be small molecules, biologics, or devices, but not necessarily in the space of cell and gene therapies (CGTs). The challenge with cell and gene therapeutics is that they usually fall under biologics, but they’re a very different type of biologic. So, many of the lessons from other biologics can be extrapolated, but the learning curve with cell and gene therapies can be steep.

This is particularly true of CRISPR products, where CRISPR has shared a long-ish lifetime in the academic and laboratory setting, but not necessarily in human therapeutics. The translation from the former into the latter is still a big sticking point in the industry.

Cell and gene therapies are often complex products - they have complex manufacturing and control and small batch sizes that may be personalized or bespoke. They also have new regulatory frameworks that are meant to accelerate development as well as alleviate the confusion around how these products will be reviewed. The problem is that health regulators are developing these guidances and regulatory frameworks at the same time as they are learning about these products and the novel technology platforms that are used to make them.

The challenges are the products themselves, the frameworks and the rate at which the entire industry grows. It’s also critical to be gathering intelligence from health regulators as they are voicing their stance on how to regulate these products. Add a few changes to the FDA division that reviews these products (now known as the Office of Therapeutic Products) and uncertainty from sponsors on how best to ask questions, and you end up with an area of unmet need.

Therapeutic developers are seeking expertise on the CGT space overall, as well as how best to interact with health regulators. Regulatory affairs, as a function, aims to answer those questions by bridging the gap between the FDA and therapeutic developers.

At what stage of clinical development should customers approach Synthego for help with regulatory issues and documentation?

Lina: Earlier is always better, but Synthego can help any client at any time in their clinical development. When clients come to Synthego early on in their discussions with the FDA or other health regulators, we can help them prepare for those meetings, including INTERACT (INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs) and pre-IND meetings. Usually the goal of those meetings are to ask the regulators if various aspects of their clinical trial, or CMC, are acceptable.

By learning from Synthego’s previous experiences with health regulators, these therapeutic developers can go into these meetings prepared, ask targeted questions and provide justification for their programs or products.

How else can partnering with Synthego help accelerate clinical development timelines for customers who are developing cell and gene therapies?

Lina: One of the things that Synthego Regulatory offers is regulatory intelligence around the CGT industry as it relates to CRISPR therapeutic development. Any learnings that Synthego can pass on to developers that may help them develop a sound regulatory strategy for their product, Synthego will pass on.

Synthego has also worked closely with bodies like the National Institute of Standards and Technology (NIST) to propose standardization of how gene editing components should be regulated. We’ve put together educational content, such as World CRISPR Day, webinars on technical topics, conference presentations, white papers, journal articles and podcasts to educate clinical developers and health regulators on Synthego, our products and the industry as a whole.

Regulatory Trends and the Future of CRISPR Therapies

As the number of CRISPR cell and gene therapies in clinical development continues to increase, so too does the pressure on the FDA to understand and approve these therapies and the need for regulatory specialists. Here, Lina explains the impact of some of the recent regulatory trends and FDA initiatives and shares her hopes and predictions for the future of CRISPR cell and gene therapies.

Do you think the recent FDA initiatives, such as the structural changes, new cell and gene therapy guidances and the Bespoke Gene Therapy Consortium, will make an impact in terms of increased development and approval timelines for CRISPR therapies?

Lina: I think some of these more public initiatives by the FDA serve multiple purposes. For one, by publicly announcing to the industry the changes they’re willing to make internally, the FDA is signaling that they are ready to adjust their frame of thinking about the regulatory frameworks necessary to streamline approvals of some of these more complex products.

They are also signaling the continuation of their modus operandi, which has always been to be as transparent and collaborative as possible. This is a regulatory body that is as collaborative as regulatory bodies get. By keeping the public in the loop about its internal changes, FDA is indicating its interest in continuing to be collaborative and transparent as it changes and grows.

FDA has also borne the brunt of the industry’s discontent in terms of slow review times and inconsistent feedback, particularly through a pandemic. The job of the FDA reviewer is at times unenviable; however, their desire to do public good, and to bring novel and effective products to patients who need them, is genuine.

What are your predictions for the next 5-10 years in the CRISPR therapy field? What changes are you hoping to see in this space?

Lina: Inevitably, there will be approved CRISPR therapeutics on the market. My hope for the future is that accessibility is improved to the point these products are not cost-prohibitive; otherwise, what’s the point of making these products if they are not reaching the right people, when they are needed? Accessibility is a big one.

Another area that I’d like to see further development in the future is a novel, or novel regulatory framework(s) that allow these products to hit the market in a much more streamlined way. This may look like a platform approach that eases the review process for regulators and developers alike.