Q&A with Cardinal Health Regulatory Sciences: Navigating cell and gene therapies through clinical and regulatory hurdles

Cardinal Health Q&A: Navigating cell and gene therapies through clinical and regulatory hurdles

Gene and cell therapies are at the cutting-edge of biomedical research, promising potentially curative options for a host of disorders such as certain forms of blindness, blood cancers and inherited diseases.

But being so new and so cutting-edge, navigating through regulatory bodies such as FDA and EMA can be challenging, with decisions on: cost and scalability; clinical focus; manufacturing and pharmacovigilance paramount to getting to market, and staying on the market. 

We speak to two experts from Cardinal Health Specialty Solutions: Michael Day, Ph. D, Director, Chemistry, Manufacturing & Controls,  Regulatory Affairs and Debra Aub Webster, Ph. D, Principal Scientist, Regulatory Affairs and Product Development, at Cardinal Health Regulatory Sciences about these issues.


Q: What are some of the biggest challenges in navigating cell and gene therapy through the regulatory process?

DAW: I think there is a tendency to lump these therapies together, when really the challenges can be quite different.  For gene therapies, I think one of the big issues is evaluating the long-term benefit, or durability of effect, based on a short-term endpoint, which is frequently a biomarker that may need to be validated.  Additionally, at present gene therapies can only be administered once.   What happens when an adolescent “outgrows” the response?   How long will patients need to be monitored?

On the other hand, patients can typically receive multiple cell therapy treatments, the response is more immediate and may or may not need to be durable.  For multipotent cells derived from amniotic tissues or autologous cells isolated from bone marrow or adipose tissue, one of the challenges that occurs here, particularly for autologous cells, is the variability from patient to patient or donor to donor, given the role of genetics or even age.

And then you have  autologous cell therapies that has been genetically manipulated, which may face both sets of challenges. So, it’s a spectrum, and I think the challenges vary – hence the “case-by-case” approach taken by regulators.

MD: FDA has begun to directly address the regulatory hurdles with the release of 6 guidance documents in July of 2018 pertaining to the development and approval of gene therapy products.  In order to be acceptable from a regulatory perspective the challenges remain largely in viral vector-manufacturing capacity, where an estimated 1–2 orders of magnitude increase will likely be needed to support eventual commercial supply requirements for many of the promising disease indications. In addition, the expanding potential commercial product pipeline and the continuously advancing development of recombinant viral vectors for gene therapy require that products are well characterized and consistently manufactured to rigorous tolerances of purity, potency and safety.

Q: How can you find your way across these challenges?

DAW: That’s a big question, but again, we have to look at each individually. Thinking about the challenges for cell therapies that are autologous and allogeneic: These are issues related to functional variability of the cell product.  In addition, the patient response to cell therapies can be more variable than for traditional therapies such as seen in the use of mesenchymal stem cells for the treatment of GvHD.  This raises the question: Why are some people responding really well, but others are not? Is it due to the functional quality of the cell or the disease state of the patient? So, the challenge here is not only establishing clinically relevant measures of potency but also teasing out the difference between responders and non-responders.

MD: Outside of the clinical view, it goes without saying that cost is also a major challenge, as well as the fact that these therapies need to be scalable. So, for cell therapies, you’re talking about needing to build a cell culture process that companies want to make scalable, but a lot of these therapies are, necessarily, individualistic. So, for example in gene therapies, a viral vector that Debra and I are working with a group on, for just about 10 patients, and this is just to get the viral vector made, costs around $1 million to $2 million. That’s for just 10 patients. That is very cost prohibitive so early on in a phase 1 study, but that’s what these companies are looking at.

The next step in terms of scalability is a universal cell host: Hospitals could carry a stock of CAR-T therapies much like a stash of antibiotics or pain meds. Moving away from the made-to-order treatments could make it easier for smaller cancer centers to provide the therapy, increasing access for patients. It could also shorten the wait time for patients to be treated, since cells wouldn’t need to be shipped to a lab to be modified and duplicated.

Q: Should commercial concerns, i.e., pricing, be factored into trial work?

DAW: I definitely think it should be: I think we’re seeing a trend in that with the clients that we help. They are starting out looking at their commercial process early on, in order to replicate it without having to make further changes down the line. I think they are also considering it in terms of how they can make it scalable from the get-go, while also thinking about how to also reduce cost overall. People are actively looking at that now, and frankly they should be, because it’s becoming one of the biggest challenges. Costs should start to come down as sponsors start to develop products that are more allogeneic-based, using induced pluripotent cells, which can have the potential to really reduce costs.

We may be seeing a shift in the cost of drug development for these therapies.  Traditionally, for small molecules, the highest cost was associated with conducting multiple large Phase 3 clinical trials with large patient population and these costs coming late in product development. For these advanced cell and gene therapies, the cost of manufacturing is higher and comes earlier.  Additionally, depending on the indication, the total cost of clinical trials for these types of therapies may actually be a much smaller percentage of total development costs to achieve approval.  However, post-approval long-term follow-up and post-marketing requirements will also need to be accounted for in total product development costs.

Q: With prices of some gene and cell therapies ranging from $500,000 to $1 million, do payers have the tolerance to bear the cost of these new type of drugs?

DAW: Well, there will be extreme social pressure for payers to consider and ultimately include these therapies. For payers to accept that, they will have to look at the total cost of treating that patient. So, if we look at the total cost of treating that patient, does it bring it down that cost over, say a lifetime? Certainly, with the CAR-Ts we will start to see that, especially if we can start using the CAR-Ts in less sick patients, by which I mean not just when they have failed three or four treatments, but at an earlier stage in their disease, such as in second-line, which again can help generate savings over the long-term.

Now, with gene therapies, the opposite can be true: When patients are treated and their lives are going to be prolonged, they are still going to require a lot of care because these gene therapies are not curing people, in this case the payers will need to be more patient centric.

Q: Is there still a shadow over cell, and notably gene, therapies when it comes to safety? And how can sponsors assure physicians, regulators and patients about long-term safety, when much of the data is short-term, given how new much of these therapies and technologies are? 

MD: I think we are seeing some signs of this thinking [long-term safety]; if you look at Kymriah (tisagenlecleucel) [Novartis’ CAR-T, which gained FDA approval in patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse], this had its initial limited approval in August last year. In May of this year, it had an additional approval for adult B-cell lymphomas, and that was based on a body of evidence from a clinical study that had been going on for more than a year. So, as word starts to get out that it works and is not creating safety concerns, it’s the stake in the ground for other products and indications. This will just snowball and if it continues to show safety, which I think Kymriah has demonstrated for these patients, as well as efficacious, you start to get that buy-in that while this is a high-cost therapy, it’s a one-time deal that could prevent a life-time of therapies.

DAW: I came from a small molecule world where the data to support introduction of new therapies into the clinic relied on animal studies and the studies needed were pretty well laid out, a formula if you will.  When monoclonal antibodies (mAbs) came on the scene, these models fell short and even with small molecules animal studies can be a poor prognosticator of safety. But, at present we don’t really have many alternatives for assessing safety of these products other than using the traditional animal models, so that’s a real challenge. As a result, both FDA and EMA are really wanting to interact with sponsors very, very early in nonclinical development, so that sponsors can capture the type of safety information these regulatory bodies are looking for to support entry into the clinic and eventual approval.

Q: Given how new some of these cell and gene technologies are, is there enough staffing expertise at the big regulators to really get to grips with these therapies, and ensure they are reviewed in the best way possible?

DAW: My experience is that FDA is doing an amazing job with not enough resources.  Given the increasing number of these potential therapies being granted expedited pathways, such as Fast Track and the RMAT designation, they will undoubtedly need increased staffing.  In my personal experience I completed a two-year post-doc, prior joining FDA as a pharm/tox reviewer. My experience was limited to bench science on intracellular second messengers.  A sponsor should consider that their reviewer may be straight out their doctoral program; their experience may be limited to gene splicing conducted in support of a thesis.  Granted, Ph. D programs teach you how to think and critically evaluate,  but it behoves sponsors to educate the reviewer about their product, to tell a coherent story, and  make it easy for the reviewer to find the data in the application they submit for review.

Q: Can this create a conservative culture within regulators? If not all staffers are fully up to speed, could they err on the side of caution with applications, rather than push forward?

DAW: I never felt that FDA was ultraconservative or overly cautious; it’s always a risk: benefit analysis. If the benefit, that is how a patient feels, functions, or survives, outweighs the risk in the intended patient population, then a therapy will be approved. FDA takes a considered approach to the risk:benefit analysis.  A review team will have new and seasoned reviewers on the review team and may also include reviewers from both CDRH and CDER in order to bring in the appropriate expertise.  If FDA does not push forward, it is due to caution based on data and not lack of expertise.

MD: FDA is cognizant that they may not have all of the expertise, or the numbers in the staff, so one of the things that they have done is to create the Oncology Center of Excellence (OCE). This is the first inter-center institute at FDA that focuses on a specific disease area rather than type of product. This strategy is breaking down some of the traditional silos that we have seen at FDA before, and it’s getting the FDA to cooperate more than before. Essentially, therapies are causing FDA to change the manner in which they operate, in what the industry sees as a very positive way. The FDA has created an internal scientific counsel which advises the OCE on certain issues, and these are steps in the right direction. I think some of these approvals that we’ve seen are a direct result of this break down of traditional silos and focusing on a specific disease, therefore increasing our communication and collaboration with FDA.

This article was created in collaboration with the sponsoring company and our sales and marketing team. The editorial team does not contribute.