Renee Boerner (Argos): CAT is still an emerging sector, but we have made great progress in recent years. Previously many of us worked to apply learnings in biotechnology and small molecule research to cell therapy, and the regulatory agencies did the same. But CAT is very different and requires a different set of rules and standards. While the regulatory agencies are working to define requirements for the sector and set standards, the guidelines are still forming. We should see much clearer guidelines in the next 10 years.

Bill Tente (Humacyte): The regulatory agencies have rapidly become more sophisticated and more collaborative when it comes to working with CAT companies. The Office of Cellular, Tissue and Gene Therapies (OCTGT) is very supportive, in large part because there are fewer unknowns. We have better assessments of safety and mechanism of action. We have potentially curative breakthroughs on the horizon. They want to support this innovation, and are improving their quantity and quality of their guidance documents and providing clearer roadmaps every year.

Koen Huygens (Consultant): One example of how flexible regulatory agencies have been regarding CAT companies can be seen in requirements related to Good Manufacturing Practice (GMP). With a small molecule, EU regulators expect companies to meet full GMP standards by Phase I. With cell and advanced therapies, it’s clear that that is often not possible, and the national competent authorities in Europe will show some flexibility case by case. However, this is currently not harmonized over the EU member states.

Richard Mountfield (Celyad): One very interesting regulatory reality is that the EU has for many years been far ahead of the U.S. in guidance and support for CAT companies. In the early years, the EMEA (now the EMA) recognized the need for the EU to be a leader in this area while the U.S. maintained its stronger focus on small molecules and antibodies. The first gene therapy product was approved in the EU. But the U.S. is clearly making CAT a focus and is catching up. Even Japan which originally had a very conservative approach is making great progress in regulatory support for CAT companies.

Tente (Humacyte): Generally speaking, the standards are not that different. Regulators will require that both autologous and allogeneic products meet certain standards in safety and efficacy. But with allogeneic products there will be additional focus on immunogenicity as well as integration and durability of the transplant. With autologous products, there will be more focus on process variation as well as characterization and mechanism of action of the product.

Huygens (Consultant): With autologous therapies, another key concern of regulators is standardization of starting materials (donor cells and tissues). The authorities will expect you to find ways to control variability as much as possible. They understand that these issues are not black and white and that is why communication with regulators is key to success. With allogeneic therapies the emphasis is put on controlling safety, immunogenicity and comparability when scaling up your process. Once again communication is key.

Mountfield (Celyad): For both allogeneic and autologous therapies the primary focus is safety, especially in oncology. In the early stages, you need to show that they won’t harm the patient. But in many areas clear standards are yet to be defined.

Boerner (Argos): With autologous therapies, the product is patient-specific and each process must be adapted to accommodate patient variability. The regulators will require CAT companies to meet a standard set of specifications with patient materials. For example, we collect leukapheresis samples with variable amounts and types of cells. Our process has to demonstrate to regulators that we can accommodate these different starting materials from patients.

Mountfield (Celyad): The best advice for CAT companies is to start planning for regulatory requirements early. They should meet with the team at the Center for Biologics Evaluation and Research (CBER) at the FDA and also take advantage of the opportunity to connect with regulators in a pre-IND meeting, which is now a key strategy for developers of new therapies. They will outline the strategy companies need to consider when submitting pre-clinical data, which can be very helpful.

Huygens (Consultant): In the EU, it is also very important to present yourself early to regulatory contacts. The EMA is very supportive and has established meetings like Innovation Task Force (ITF) and Scientific Advice meetings to enable this. These are opportunities to present your product development strategy and to get feedback from the agency where your CAT product fits from a regulatory perspective. You can also get their thoughts on any alternative development approaches you are considering at this stage.

Boerner (Argos): It is key to remember that when it comes to CAT programs, “normal” often does not apply. For example, animal models are generally not possible. You need to outline any special considerations in your program early. To do this you need to take advantage of opportunities to meet with regulatory contacts early and often. One advantage is that regulators are used to the unique challenges that CAT companies can present and are willing to work through them.

Tente (Humacyte): It can be very helpful to engage with a consultant to help guide you through the earliest stages of the regulatory process. They can often provide innovators with essential insights and advice at the conceptual stage.

Mountfield (Celyad): The U.S. clearly wants to stay ahead of the curve in cell therapies, and so they are generally very open to dialogue early. We have found that the regulatory process in the EU is bit more formal in the early stages. They follow a standardized process before companies can advance to sub committees that focus on cell therapy. But the Committee for Advanced Therapies is a very important and helpful resource, and once companies advance to the national authorities, the process becomes more flexible.

Tente (Humacyte): The most common errors that CAT companies make in planning for regulatory needs relate to understanding their own process. They don’t have clear answers regarding the quality of their materials, and they don’t use sufficient analytical tests to characterize the therapeutic entity. They still have work to do to understand the correlation between mode of action (MoA) and potency. Many companies don’t even realize that there are now many consensus testing options available from groups including the U.S. Pharmacopeia (USP), American Society for Testing and Materials (ASTM), National Institute for Standards and Technology (NIST), American Society of Gene Therapy (ASGT) and International Society for Cell Therapy (ISCT).

Mountfield (Celyad): With both the EMA and the FDA, you must demonstrate that you can control the manufacturing process and achieve target goals in quality, purity and reproducibility.

Boerner (Argos): It’s not a clear mistake per se, but CAT companies should focus on choosing reagents that can support their path to commercial manufacturing, or work with vendors who can support them through commercial stage. Many vendors can supply research grade, but not cGMP grade. That can become an issue as a development program advances.

Huygens (Consultant): Another common error can be based on the use of new technologies. In CAT, the applications of different technologies are expanding rapidly. Companies must help regulators to understand how these technologies work, what advantages and risks they present, and how a development program will consistently mitigate any risks. If you are adapting technologies used in biopharma, you need to clearly outline how they will fit in your CAT process.

Tente (Humacyte): When the regulators make a recommendation, companies are wise to take it seriously. In my experience, many regulatory problems occur because companies ignored specific input or advice provided by regulators. Whether it is based on a gap in science or a personality conflict, this is almost never a wise decision and is often unnecessary.

Boerner (Argos): Another mistake I see is that innovators don’t take advantage of the established forums focused on CAT issues, such as the Association for Regenerative Medicine (ARM). There are now several groups working with regulators to develop more efficient and streamlined pathways to regulatory review. We are still in a period when only a few products have advanced to late stage development and commercialization, so these alliances can be a major resource.

Tente (Humacyte): In addition to what you present to regulators, you also want to focus on how you appear in these meetings. You want your positions to be credible and backed up by data wherever possible. And you don’t want your innovations and solutions to look like you are cutting corners. This is one area where consultants who have IND and BLA experience can really help.

Huygens (Consultant): For companies outside the EU working with regulators in the EU, many are new to the role of the Qualified Person (QP). EU regulations require that each batch of product is certified by the QP prior to release for use in clinical trials or the commercial market. This is a professional who can facilitate developing the Investigational Medicinal Product Dossier (IMPD) and help in managing product development changes (e.g., change in release specs) while maintaining compliance to the product specification file. The CAT company and the QP should work closely together during clinical development and provide the QP with the necessary data to make an educated assessment. This is a fully independent decision and the QP takes personal responsibility for making a product available in clinical trials or to the market.

Tente (Humacyte): Another big miss is when companies don’t maintain a detailed summary report for a development program. This should be updated in real time and will be needed to support regulatory submissions including the IND. Companies should refer to guidance and standards for summary reports from ASTM, NIST and other industry organizations.

Mountfield (Celyad): Regulators want to see clear evidence of reproducibility early. Companies don’t have to show that they can achieve commercial scale production early, but they do need to confirm reproducibility.

Boerner (Argos): The FDA clearly understands the issue of variability in autologous therapies. But that does not mean that CAT companies don’t have to address it. And if it’s not addressed by Phase III it may be very difficult to get to approval without a comparability study.

Huygens (Consultant): In the EU, companies have a good bit of flexibility in manufacturing through Phase I and into Phase II. By Phase III, the process must be consistent and all questions related to supply chain must be addressed to achieve a product and a process that is robust enough for the commercial phase.

Tente (Humacyte): Certainly prior to the initiation of a pivotal Phase II clinical trial. I know of one company that introduced a manufacturing change in a pivotal randomized trial that had a significant effect on the biological characteristics of the product. The impact on timeline and costs forced them out of business. While that might be an extreme example, changes at any stage can increase the risk of delays or a clinical hold that can be devastating.

Tente (Humacyte): The risk of variation is the biggest distinguishing feature of CAT companies compared to small molecule or biotechnology companies. Things can be done to mitigate variation. First you must confirm that materials are of suitable quality and can be reliably sourced; eventually you must confirm that they can be obtained cost effectively at commercial scale. You also need a very strong product characterization tool box, recognizing that process changes or scale increases can be vetted through thorough product comparability testing. Companies must be aware of all of the applicable, state of the art methods and platforms to support product characterization.

Mountfield (Celyad): With small molecules, it is usually relatively easy to demonstrate control of the manufacturing process to achieve target goals in terms of product purity and consistency. Even with monoclonal antibodies, technology has advanced to make this much easier to achieve. Regulators are looking for that same level of confidence in the CAT manufacturing process and it is up to the companies themselves to demonstrate that they can achieve their goals.

Boerner (Argos): The regulatory strategy is a challenge when you advance from research to commercial stage for all therapies, but the considerations are more significant in CAT. One of the key challenges is based on the fact that we are still defining the necessary guidelines for CATs and building the infrastructure to support development programs effectively.

Huygens (Consultant): Compared to small molecules CAT products are complex and fragile and require special attention when developing supply chain solutions to get the product to the patient. I have seen very complex supply chains in late stage that would not work in a commercial setting. Companies really need to define what product the end user wants: a therapeutic solution that is easy to handle while maintaining product quality.

Mountfield (Celyad): Even in the early years, a company will need someone in-house to manage and plan for the regulatory strategy. This person should reach out to consultants as needed – and it is key to work with consultants with cell therapy experience. This is the only way for a company to know what they don’t know about the process. Longer term this may not be necessary. At Celyad, we have an internal team with regulatory experience in cell therapy that is guiding our efforts.

Boerner (Argos): Consulting in CAT is evolving, but there are not many consultants who have helped companies to reach either approval or commercial stage production. That is why different industry organizations and alliances can be especially helpful.

Tente (Humacyte): In addition to consultants with product and process development experience, there are two additional areas where consultants can play an important role with CAT companies early on. First is in handling the electronic submissions process. Electronic regulatory submissions are now established and can make the process much more streamlined, so companies should invest early in building this capability. In addition, they should identify an experienced regulatory agent as a point of contact who can manage regular communications with regulatory contacts. A good regulatory agent will have direct relevant experience including a history of work with the Office of Cellular, Tissue and Gene Therapies (OCTGT).

Huygens (Consultant): Early on consultants, preferably those with cell therapy experience, play a key role in developing the required documentation for the regulatory review process. They can help a company to understand how their process can meet GMP requirements and how to translate data and science into a clinical trial application (CTA). But by Phase III, these capabilities should mostly be in-house.

Mountfield (Celyad): The important news is that the regulatory climate is now becoming more streamlined and is conducive to providing effective support to CAT companies at every stage, especially in the early years. Consultants can play an important role in helping CAT companies to understand the changes in the regulatory process and the resources available to help them succeed.