Regenerative Medicine Companies Pursue Unique Regulatory Pathways

The field of regenerative medicine is well underway, with many emerging biopharmaceutical enterprises focusing on numerous disease indications. With this competition comes the need to diversify target disease indications, as well as generate more compelling data for both regulators and payers. Additionally, developing physician-centric stem cell administration procedures during clinical trials appears to position the therapy for wide adoption and utilization post-approval. Further, getting to market first is critical, and regenerative medicine companies, such as Pluristem, have taken unique regulatory pathways to advance their therapies. In this interview, Yaky Yanay, CEO of Pluristem, will elaborate on his experience and the strategies Pluristem implemented in regenerative medicine clinical trials.

Moe Alsumidaie: As a regenerative medicine company, what regulatory pathways are you pursuing and what challenges did you experience when setting up the studies using placenta-derived stem cells?

Yaky Yanay: We have been one of the first companies that engaged with the FDA for improving real allogeneic cell therapy products. A key step is informing the FDA that this is not a stem cell product-these are adherentstromal cells, which do not differentiate or replace patient cells; the mechanism of action is an endocrine/paracrine effect. Ten years ago, regulators had some concerns about potential homogeneity issues and how cellular products functioned. I’m glad to say, a decade afterwards, the FDA stands behind cell therapy. Regulatory agencies use terms like cell therapy, regenerative medicine, not “stem cells”, which is good.

MA: You are developing a therapy for protection from acute radiation syndrome before exposure takes place. As the study cannot be performed in humans, how do you conduct this trial, and does it have an equivalent to Phase I through Phase III in human subjects?

Yanay: We are developing a product for acute radiation syndrome with the NIH, the DoD, and in part in Japan with Fukushima’s university and hospital. We received special designation from the FDA called the Animal Rule. When you cannot run clinical studies for medical and ethical reasons, as in exposure to radiation or certain chemicals, the FDA allows you to do efficacy studies on animals. You have to prove efficacy in small animal and large animal studies-mostly non-human primates-and you have to see the efficacy and a very detailed mechanism of action. The bar is much higher than in usual clinical studies, where you either meet the primary endpoint or not. Here, you need to put much effort into basic science. The Phase I equivalent is the small animal study, and the Phase II equivalent is a pilot study in a large animal model, as the pivotal study on a large animal model. They will also ask for safety in humans, so in parallel, we are conducting a Phase I study treating hematological disorders, like patients who have bone marrow deficiencies after transplantation. This is part of our strategy, across our pipeline we target indications using unique regulatory programs that will allow us fast-tracking and to get quickly to market with a relatively small number of patients.

MA: Is there a particular reason why you are pursuing that? Do you intentionally target indications with a limit on human trials? What are the limitations on normal pathways such that you chose to use this other pathway?

Yanay: It started the other way around. We found that the cells are very efficient countermeasures for radiation. If you inject the cells post-exposure to a high level of radiation, instead of 30% survival in the placebo, we saw close to 100% survival in the treated group. In these cases, when you cannot do clinical studies in the locations of nuclear catastrophes, the FDA developed this special pathway.

MA: In your human clinical trials, many things can go awry. What operational and logistical challenges did you experience with your study’s design and how did you overcome those challenges?

Yanay: One of our main goals, from the beginning, was to have a harmonized protocol between the FDA and the European Medicines Agency (EMA) because this is new technology, and we want to make sure that both regulators will comply with what we suggest. Luckily, we found a protocol that both of them agreed on for our Phase III studies. We invested time in developing the capability to manufacture high-quality cells with batch-to-batch consistency. However, with cell products, you must ensure that the cells can be administered simply. You do not want medical teams to spend too much time on a very complicated procedure; otherwise, they are not going to use it. So, we designed cells in a vial; the physician just has to thaw them and inject them. The medical team are the clients in this case, and you have to design the product that will work for them. We even built a thawing device to easily replace thawing in a water bath.

MA: You have turned this into something that we call physician-centric: the design of the product matches the site’s operations, so it is easier to administer with fewer mistakes or issues. Please elaborate on this.

Yanay: It is the philosophical approach of, where do you see the product ending? Many companies think that they are done with manufacturing their product once it leaves the facility. At Pluristem, we understand that we can say that we completed the product only when it is injected into the patient’s body. We need to take full control of each of our parameters until then. Manufacturing is critical, and we are using our 3D bioreactor technology-the most advanced technology that will give us full control over the manufacturing process to get the same cells every time. We also developed cold chain logistics with our partners Fisher BioServices to make sure that it is fully controlled and monitored. Through the physicians, we worked with patients to understand what they need: how many injections to use, injection volume, what patients can tolerate. So we check all of these parameters to make it simple for the medical team.

MA: Please discuss your clinical trial outsourcing model.

Yanay: At Pluristem, we do not use CROs for Phase I or Phase IIa trials. We have a full-blown clinical operational team that runs the studies so the organization is trained to understand what needs to be done. Moreover, when you work with CROs for Phase IIb or Phase III, you need to know what to ask and their key performance indicators. In addition to our full clinical operational team, we also have a quality system and quality personnel that work closely with the CROs. You have to be at the sites, meet the physicians, listen to the coordinator, see what is going on. These are your patients, not the CRO’s patients.

MA: From a clinical development strategy standpoint, how do you maximize the results of your data through clinical research, and can you apply the data gain from failed studies to advance studies in other disease indications that you are pursuing?

Yanay: I prefer to apply data from successful studies. From very early, Phase I, we collected more data than needed. It cost us more, but it gave us a much broader understanding of what we see. Moreover, we can apply what we saw in future studies. We also make sure that we understand how the mechanism of action looks and if we need to change something in the design for future studies. We apply this now in Phase III studies. There are no shortcuts here.

MA: Does this data help when you apply for payer coverage?

Yanay: We anticipated that collecting economic parameters is as important as clinical endpoints. In each study, we collect every possible economic parameter. Regenerative medicine is about the patient, but it is also about the system. If it is not able to reduce the healthcare cost, it will be challenging to implement, so this is the promise of what we do. We are going to impact the quality of life, we are going to regenerate patients’ ability to overcome chronic diseases, but we are also going to save much money for the system itself, and this is what we are targeting.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials