Roundtable Part 3: In your opinion, what are three reasons slowing the rollout of more cell and gene therapies to patients?

High cost to not only develop, but to manufacture; unique ancillary/raw materials required with limited standardization in testing by manufacturers and standards in Pharmacopeia; and time in the clinic for slower progressing disease (e.g. neurological degenerative diseases).

Organizations involved with the analytical testing of CGT products are facing several challenges with regard to the resources needed to support the unique needs of these programs. In some cases, instrumentation that had historically been used in research settings are being reconsidered in a GMP capacity. Even as these new GMP systems are coming on board, the demand is outpacing the capacity in some cases. Development of methods and validation plans (instrumental or method validations) are requiring a deep understanding of both the science and of the regulatory needs of CGT. In situations where an instrument is being used in a novel way, or a material poses particular challenges to a method, teams are blazing new trails as they determine approaches and navigate obstacles that are normal parts of this already lengthy process. Small batch sizes and limited material for development studies further complicate the process and these efforts.

One of the most important reasons is speed to clinic. A lot of indicators and the projects have to be delivered in a fresh state. There is very little time between the time it is put in the final container and closure to move it to clinic so that it can be administered. Often, you are not even given enough time to complete all the testing, and sometimes it is even agreed upon to move it at risk. However, this doesn’t put the patient in jeopardy. What has happened before that time is that there has been in-process testing and there are many indicators and analytics before the final CoA to grade or judge how well the process is going — from beginning of the process, to the end of the process and to the final formulation of the product before moving into the clinic.

A main issue impacting innovation and advancement in gene therapy is manufacturing technology and the challenges that are involved in the production of such complex products, including the need for highly specialized manufacturing facilities. Costs associated with research and development along with the healthcare system requirements that must be in place to treat patients with these therapies are also factors.

As you know, the promise of gene therapy technologies is enormous, putting transformative treatments for many rare diseases within reach. One area of concern is the fact that the costs and other challenges associated with development could potentially place them outside the reach of health care systems in developing nations. However, recent gene therapy approvals demonstrate the continued momentum of this promising new area of medicine, and the potential of these products to address unmet medical needs provides hope for the future. I believe that we have the ability to overcome these challenges to inform future product development where we have widespread commercial production ability on a larger scale, with the potential of improving the current standard of care for many diseases – some of which do not yet have approved treatments.

The key things slowing the growth of cell and gene therapies are the ability to scale (i.e. adoption, manufacturing, supply chain), stringent regulatory control and reimbursement for these very expensive therapies.

To begin, the mechanism of disease must be discovered. This is often a defect in a single gene, either point mutation, deletion or rearrangement. It may take many years for a skilled discovery laboratory to elucidate the molecular basis for therapy.

Additionally, there are resource and supply chain challenges. Plasmid DNA, for example, is a critical raw material needed to produce cell and gene therapies, but the rapid emergence of these therapies has dramatically increased demand for plasmids, creating a manufacturing ‘bottleneck’.

Furthermore, to develop, manufacture and test these therapies is complex, and requires many different materials and intricate steps. For autologous therapies, vein to vein time is short, which further adds to this complexity. For viral vectors, the transfection step varies from one product to another and should be optimized to generate the highest yield and quality.

Additionally, there are upwards of 30 release tests required for gene therapies to assure safety and efficacy, while clinical trials are expected to reveal therapeutic durability, taking time. While gene therapy vectors may be administered directly, cell-based therapies require further steps in the collection, modification and infusion of the cell therapy. In comparison to mAbs or small molecule drugs, product yield tends to be relatively low, making these treatments expensive and inaccessible. This is where experienced development and manufacturing partners can help by leveraging expertise in established processes, and experience from the multiple programs they have worked on to help scale and commercialize new modality treatments.