In our previous blog post, we discussed the revolutionary immunotherapies known as chimeric antigen receptor T-cells (CAR T). The first CAR T therapies, axicabtagene ciloleucel (Yescarta™) and tisagenlecleucel (Kymriah™), were approved in 2017 by the US Food and Drug Administration (FDA). The significance of these approvals was clear, with FDA Commissioner Scott Gottlieb noting in his October 2017 press release that they represent milestones “in the development of a whole new scientific paradigm.”
That CAR T treatments are finally reaching the market after decades of research is exciting, indicating the potential for better, more personalized cancer treatments. However, as often happens with ground-breaking products, the most direct developmental and regulatory path for these therapies has not always been clearly defined. Indeed, regulatory agencies have had to adapt their own thinking along the way and, in the wake of these new approvals and as additional product innovations are made, it is certain that their processes will continue to evolve.
As such, if you are involved in the development of new CAR T therapies (or any novel therapy for that matter), it is critical to understand the current regulatory landscape and its potential limitations, to anticipate regulatory and clinical hurdles that may arise during development, and to adapt proactively and efficiently to new regulatory developments.
In the current post, we present three key hurdles that stand between CAR T as a novel and exciting concept to CAR T as an approvable therapy, along with strategies to help overcome these hurdles.
Three Hurdles to FDA Approval
1) FDA Guidance & Communication
FDA guidance documents represent the FDA’s current thinking on a wide array of drug development topics. Unfortunately for those developing novel therapies like CAR T cells, available guidance from the FDA can be relatively sparse, partially because the FDA may still be determining its own best practices. Certainly, guidance documents exist that cover cellular and gene therapies, but most often these documents paint with a broad brush, with no specific recommendations for CAR T products. While the FDA is working to expand their library of guidances, the large number of actively recruiting CAR T-based clinical trials indicates an immediate and unmet need for additional FDA input.
How to Prepare: In the absence of formal guidance documents, leveraging existing information in the public domain can help put you on the right track. While this may not answer all of your questions and there may be nuances in your particular program that present unique challenges, gaining insight into what has worked in the past can still pay great dividends and prepare you for productive interactions with the FDA.
One of the best places to look for this information is on the FDA’s website. For cellular and gene therapy products, the FDA’s Center for Biologics Evaluation and Research (CBER) maintains a list of approved products that includes links to additional content (for other types of drugs, try searching Drugs@FDA). There you will find a wealth of information about each product, often including the summary basis of approval (SBA), individual subject-level reviews (e.g., clinical pharmacology, toxicology, manufacturing), information requests, risk evaluation and mitigation strategy documents, the approved product label, and so forth.
While these resources can be very helpful for informing your development and regulatory strategy, it is also critical to gauge the FDA’s thinking on your particular product and development program. One of the best ways to do this is to engage directly with the FDA in the context of a formal meeting. For CAR T and other cellular and gene therapies, you can reach out to the Office of Cellular and Gene Therapy Products in CBER to request a meeting appropriate for your stage of development (e.g., Pre-IND, Pre-BLA, End-of-Phase, Type C). During these meetings, the FDA can provide critical, on-the-record insights on a wide range of topics including clinical trial design, safety considerations, the sufficiency of your preclinical program to support entry into clinical trials, regulatory strategy, and a host of other topics.
Finally, careful consideration of the nuances of your product that may present unique developmental or regulatory challenges is essential. For example, if your CAR T therapy is to be co-administered with another molecule or using a novel delivery device, additional regulatory requirements may apply (e.g., device and combination product regulations, additional safety assessments). Especially in these and related situations, we advise our clients to begin their interactions with the FDA early and to keep the lines of communication open. Doing so can help prevent costly delays and missteps that could derail your program.
2) Isolation, Manufacturing, and Distribution
Unlike most drugs and biologics, current CAR T therapies (with the exception of certain allogeneic “off-the-shelf” products in development) use a person’s own cells to create an individualized treatment. Typically, a patient’s cells are harvested at the clinical trial site, transported to a laboratory (i.e., manufacturing site) where they are modified (often using a viral vector to introduce the CAR genetic material) and expanded, shipped back to the clinical site where they may be stored temporarily, and then infused back into the patient usually several weeks after the original isolation. Each step of this process adds additional layers to an already complex system. Potential variability in key product quality parameters (e.g., cell viability, potency) and how these are impacted during storage and shipping are key considerations and may attract additional regulatory scrutiny.
How to Prepare: Beyond gathering information about existing therapies and engaging with the FDA, it is important to generate appropriate plans for each aspect of the clinical and manufacturing process from original isolation through re-infusion and to anticipate potential problems along the way. Clinical site training is a key aspect of this and is often formalized as part of the Risk Evaluation and Mitigation Strategy (REMS) submitted with the marketing application (BLA). Shipping/storage protocols and detailed manufacturing plans are another essential component, as are studies assessing the effectiveness of these plans for maintaining product quality. The testing strategy should include not only “ideal” conditions but also the impact of potential deviations such as unintended shipping delays and suboptimal storage conditions.
3) Product Safety and Long-Term Follow-up
In our previous post, we described the toxic side effects of CAR T therapies, including cytokine response syndrome and on-target/off-tumor toxicity. The substantial risks demonstrated by approved CAR T therapies also include multi-organ failure, late onset leukemia, neurotoxicity, and brain tumors. These toxicities are likely to be associated with any new CAR T therapy, and, as an additional complication, preclinical models are often incapable of identifying the full profile of side effects observed in humans. For these reasons, FDA reviewers will look for a thorough analysis of potential risk and risk mitigation, so that side effects can be rapidly and appropriately addressed.
In addition to acute side effects, it is also necessary to consider long-term safety outcomes. As cellular therapies, CAR T treatments have long-acting biological profiles. It makes them effective cancer treatments, but also indicates a potential for delayed adverse events, immunogenicity concerns, and negative effects on normal cell growth and development. As you prepare to transition to the clinic, consider these risks and the duration of long-term follow-up that will be required. Kite Pharma (now part of Gilead Sciences; YescartaTM) and Novartis (KymriahTM) are both managing long-term follow up studies to fulfill postmarketing requirements and must collect patients’ safety information for 15 years. This type of long-term study is costly but making such a commitment to understanding the full safety profile of the therapy is critical for regulatory approval.
How to Prepare: Early-phase clinical trials should be carefully designed to ensure a comprehensive safety assessment, efficient product delivery, and optimal clinical and manufacturing procedures to maintain product quality and safety. Consideration not only of commonalities with existing therapies but also of the unique aspects of your particular product that may necessitate additional safety assessments is an important aspect of this. These considerations, along with experience gained during clinical development of your product, will help inform the eventual REMS that will be submitted with the BLA.
Be prepared for long-term follow-up. Late stage clinical trials will likely need at least 1 year of follow-up data prior to commercial approval, and post-market follow-up periods of up to 15 years should be expected. There is some potential for this period to be shortened based on the mechanism of action and biological profile of the product, including persistence of cells in the patient, duration of expected response, and expected survival rates of the population. Early discussion with the FDA and careful design of early stage clinical trials may allow you to reduce costly long-term follow-up.
CAR T therapies represent an exciting era of personalized medicine, and we will undoubtedly see new CAR T drugs continue to reach the market. Understanding the hurdles to developing these therapies, such as a lack of CAR T-specific FDA guidances, the complexities of manufacturing and distribution, and potential safety concerns coupled with the need for long-term follow-up, will increase your chances of success and help get your product well on its way to commercialization.