The US Food and Drug Administration’s (FDA) guidance documents offer sponsors greater clarity on trial designs and control strategies that could potentially accelerate the development of in vivo CAR-T cell therapies.
Chimeric antigen receptor (CAR)-T-cell therapies are personalised immunotherapies used to treat cancer by utilising a patient’s own cells. Currently, all approved therapies are ex vivo, meaning they take place out of the body, which can end up taking two to six weeks. In vivo therapies can bypass many of the limitations associated with ex vivo CAR-Ts, particularly the lengthy vein-to-vein time, as dosing is done through an off-the-shelf vector.
The new FDA guidance outlines acceptable trial designs and potential control types, including the use of external controls which can help companies conduct and enroll trials, particularly when investigating therapies in more rare sub populations.
Dr Maurits Geerlings, CEO of NanoCell Therapeutics, tells the Clinical Trials Arena how he anticipates in vivo CAR-T cell development will accelerate due to these new guidelines.
Editor’s note: This interview has been edited for length and clarity
Abigail Beaney (AB): Delving into these FDA draft guidances, what do they really mean for the development of in vivo CAR-T cell therapies?
Maurits Geerlings (MG): It means a lot in terms of the clarity and flexibility that it provides because this is a new field. It touches patient populations that, on the one hand, are smaller patient populations, but also provides options for larger populations, which is the benefit of in vivo. While it is well known that certain indications, such as DLBCL and follicular lymphoma, are considered maybe smaller populations because of the reach of ex vivo CAR-T being limited, the in vivo approach provides the potential for it to be much larger for patient populations.
These guidelines are going to be important in providing that benefit for patients, because they help accelerate the development towards approval and post approval. There is some flexibility through tools that are provided that allows for a faster approval path, when you compare it with other regions. One example is Europe, which is stringent with the requirements getting to approval because they need more data, whereas the FDA seems to be more flexible with post approval monitoring mechanisms.
AB: What kind of clarity does the guidance provide? What aspects of study design does it help clarify for companies like yours operating in this space?
MG: What is so important for us is to know is that the FDA is open to working with innovative trial designs, such as the adaptive design or external controls, and these are very important for in vivo CAR-T.
The patient centric design, or master protocols, are important tools that the agency has spelled out to be open and willing to work with. As NanoCell is looking to launch its initial study as a basket trial, you really need those tools.
The other very important matter of clarity is designations so that we have access to rolling reviews, wiggle room with some endpoints, or priority slots. The interaction and openness from the agency are very important, and that has been spelled out in those guidelines.
AB: How can this guidance help with running alternative designs for subpopulations of patients?
MG: You can capture populations of similar indications with this guidance, which will help with running trials. For example in follicular lymphoma, DLBCL and acute lymphoblastic leukaemia, you can capture smaller patient populations which can then be put into the same basket trial, and that is where the master protocol that is spelled out in the guidelines is relevant. In the same way, we can tap into certain solid tumour indications, such as ovarian cancer or glioblastoma, amongst others, while these sub-populations can be small patient populations, these trial designs will help expand patient access.
AB: Do sites have the capabilities in both time and equipment to start taking on more of these trials?
MG: Yes, I do, because what is so nice about this whole evolution of CAR-T is it started as an autologous proposition, and as companies started working on allogeneic approaches, the strong push was to get this more in the outpatient setting. This was led by companies such as Novartis and others that started in the CAR-T space, which allowed non-highly specialised hospitals to be involved in clinical trials, so more in an outpatient setting.
With in vivo, the vision is that you can get a step farther, you get deeper into the community centres that would just have an ICU but not necessarily the apheresis facility. The fact that you don't need apheresis allows you to expand the pool of hospitals that would qualify. If eventually we can show you do not need an ICU, these trials can even get further into the community's centres, with a regular oncologist treating patients. But those are steps that over time, can be made as clinical experience is accumulating,
AB: How does this guidance support the US as a space for in vivo CAR-T development?
MG: This guidance gives a level of comfort in the life sciences community to really take advantage of what the US has to offer. There has been a lot of talk about going to China for IST trials; that also comes with a level of uncertainty, especially when you develop novel treatment modalities. If something goes wrong, then it may affect your entire value proposition, which may leave you with a programme you can no longer develop anywhere. This could be if a patient death occurs in the trial, which may have happened for the wrong reasons because you didn't have that connectivity with the clinical sites and the control on the execution of the clinical trial. These guidelines help companies refocus on the US.
