Cell and gene therapies: Cutting edge science, new clinical and regulatory challenges

After decades of slow and steady progress, cell and gene therapies are continuing to experience important breakthroughs. Gene therapies, like Luxturna , have proven that it’s possible to not just treat symptoms, but to correct and potentially cure the underlying genetic cause of disease. Similarly, cell therapies such as cord blood and TEMCELL® HS Inj . (the first allogeneic cell therapy launched in Japan) are proving the power that human cells have to treat disease in truly transformative ways.

Together, these cutting-edge therapies have the potential to slow disease progression, improve outcomes, and in some cases, potentially cure an array of illnesses ranging from blindness and blood cancers to inherited diseases.

However, specifically because these therapies are so new and so cutting-edge, it can be challenging for their developers to navigate through the complex clinical, commercial and regulatory hurdles that may be quite different than the challenges faced by traditional therapies.

Here, we explore some of the key clinical and regulatory questions that pharma companies should consider when developing cell and gene therapies.

• For gene therapies, how will you demonstrate durability?
  
  One of the most significant issues for gene therapies is evaluating the long-term benefit, or the durability of effect, the therapy offers. Because gene therapies can currently only be administered once, developers may need to consider the impact that a patient’s growth – from, for example, childhood to adolescence to adulthood – may have on the durability of the patient’s response to the therapy.
  
  In some cases, a sponsor may need to demonstrate what percentage of a patient’s gene-edited cells are needed to maintain the clinical benefit.
  
  In other cases, the approval of a gene therapy may be conditional, based on the sponsor’s ability to develop a biomarker that can validate and predict clinical benefit.
  
  In addition to providing data that supports initial approval by regulatory agencies, sponsors should also be prepared to collect data that demonstrates the therapy’s longer term, favorable impact on the total cost of patient care. This might mean designing clinical trials that include other aspects of clinical care, in addition to a primary outcome measure. The use of patient disease registries and registries specific to a technology may prove useful in defining long-term efficacy and safety.


• For cell therapies, how will you determine relevant potency measures that are predictive, or at least correlated, with the mechanism of action and potential efficacy?
  
  Potency measures can be highly variable depending on the cellular therapy. In some cases, the mechanism of action may not be fully understood and it will be difficult to link an in vitro potency assessment with clinical efficacy. In order to secure regulatory approval in these cases, sponsors would need to select a potency measure that accurately predicts or is associated with clinical outcome.
  
  In other cases, the mechanism of action may be well understood – but the challenge may lie in setting potency specifications in the context of donor variability with respect to the starting material.
  
  Additionally, because of variability in patient response in each of these cases it can be difficult to correlate potency assessments with clinical benefit – particularly with limited clinical data. This may require more restricted patient populations and the use of complex clinical trial designs.


• How will you develop a scalable manufacturing process?
  
  Cost and scalability are also major challenges for developers of both cell and gene therapies. For autologous cell therapies, a primary financial challenge is how to build a cell culture process that is scalable, even though these therapies are, necessarily, individualistic.
  
  Some developers are also exploring the next step in terms of scalability – a universal cell host that could be stocked by hospitals, much like hospitals stock antibiotics or pain medications. Moving away from made-to-order treatments could make it easier for smaller cancer centers to provide these therapies, which would improve 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.
  
  It’s growing increasingly important to work very early in the development process to explore ways to make commercial processes scalable – while also identifying ways to reduce costs overall.


• How will your cost model change?
  
  Traditionally, for small molecules, the highest drug development costs have been associated with conducting multiple Phase 3 clinical trials with large patient populations. These costs typically come late in product development. For advanced cell and gene therapies (depending on the indication), the total cost of clinical trials may actually make up a much smaller percentage of total development costs. However, manufacturing costs are higher and come earlier for cell and gene therapies. Post-approval, long-term follow-up and post-marketing requirements also need to be accounted for in total product development costs. Sponsors will need to adjust their cost models to ensure their products are adequately funded during these critical phases of the lifecycle.


• How will you demonstrate safety to the FDA?
  
  With traditional, small molecule therapies, data to support the introduction of new therapies into the clinic relies primarily on animal studies. But animal studies can be poor predictors of safety for cell and gene therapies, which may not activate in animals as they would in humans.
  
  Unfortunately, there are few alternatives for assessing safety of these products – and that’s a real challenge. Demonstration of safety may require development of an analogous primate or mouse product; or the development of a transgenic animal model. Because there’s no blueprint for demonstrating the safety of cell and gene therapies, it is important to work with health authorities like the FDA and EMA very early in the nonclinical development process to create clear expectations regarding what kind of safety information sponsors will be expected to provide to support approval.

Although developers of gene and cell therapies face unique challenges on their path to commercialization, they must do so while also remaining focused on addressing the key challenges that are central to any development process: The need to educate reviewers about the science behind their products, the need to make it easy for reviewers to find and understand the data that proves both efficacy and safety; and the need to tell a coherent and compelling story.

Indeed, the increasing potential of these advanced therapies is evidenced by the number of Regenerative Medicine Advanced Therapy (RMAT) Designation Requests received and granted by the Center for Biologics Evaluation and Research. While no RMATs have been approved at the time of this post, 16 of the 47 requests for designation received in 2018 were granted , and four are still under consideration. As more sponsors identify ways to effectively grapple with the unique challenges facing cell and gene therapies, we believe the number of approved RMATs will only continue to increase.