Early Engagement Strategies to Set Cell & Gene Therapies Up for Success

Cell and gene therapy product development is complex and ever-evolving. Bringing a product from the research bench to the bedside can be a very challenging journey. A group of our experts sat down to discuss what key elements drug developers need to focus on in the early stages of their cell and gene therapy program that will set them up for future success.

Featured Experts:

• Jonca Bull, VP Value & Development Consulting, Evidera, a PPD business
• Gene McNally, VP Value & Development Consulting, Evidera, a PPD business
• Richard Dennett, Senior Director, Regulatory Affairs
• Duu-Gong Wu, Senior Director, Regulatory Affairs

When working in the early stages of development for a cell and gene therapy product, what are the key areas developers need to focus on to set their product up for future success?  Is early stage too soon to be thinking about commercialization?

Richard: As a central context, “you need to know where you’re going in order to be able to get there.”  Beginning with the end in mind may have become cliché in drug development, but it is absolutely imperative for gene therapy. Because of the need to solve complex manufacturing, safety, evidence and payment issues, early planning forms an important strategic grounding point for cell and gene therapies when compared to other products. Having a commercial vision must be an objective from the outset and can help form a critical path of understanding that is sometimes overlooked by cell and gene therapy developers. As a central focus, it is key to establish the target product profile, which holds what is essentially a big bang of key development information.

Gene: Agreed, I think it is never too early to consider the attributes of the commercial image product.  One of these critical attributes is the titer of the cellular product or the copy number for the gene transfer construct which equate to the amount of product produced. Failure to achieve acceptable titers/copy numbers (relative to the anticipated effective dose) can result in backtracking to optimize this late in development, which can lead to repetition. 

Duu-Gong: In the early phases of cell and gene therapy development, special attention should also be paid to how to manufacture a product with consistent product quality and to the safety of materials from biological sources. For example, the controls of replication competent viral particles in the viral vector used for the transfer of target genes and the prevention of potential contamination of adventitious agents (viruses, mycoplasma, etc.) are essential for the safety of the cell and gene therapies.

How do developers best determine their CMC plan for a cell and gene therapy product and what manufacturing considerations need to be taken into account to help ensure a product gets regulatory approval for a clinical trial?

Duu-Gong: Because cell and gene therapies are made up of many different classes of products, each CMC plan need to be product specific and developers need to understand the unique CMC requirements. Key success factors that should be included for successful regulatory approval are:

• A scalable manufacturing process
• Prevention of contamination by adventitious agents
• A robust characterization and release test program

For example, unlike the chemical drugs, the donor qualification and proper tests to control the stability of cells during separation, manipulation and shipment to clinics for administration to patients needs to be considered.

Richard: A key takeaway from my perspective is to live and breathe the regulatory guidance for cell and gene therapies. Manufacturing considerations, as for any product, will encompass both the development and GMP clinical manufacture, but including cell and gene therapy-specific characterization, associated testing, control and release in meeting with a quality driven product required to meet regulatory compliance for approval of the clinical study is critical. For advanced therapies, and in the case of cell and cell-based gene therapies, initial donor testing and eligibility and procurement of the source material is a requisite factor along with proper product demarcation and sometimes novel or special formulation of the product. 

What are the critical factors in a gap analysis for a gene therapy that will either help foster a go/no-go decision or build a strong story for investors and help secure a next round of funding to advance development?

Jonca: A clear vision of proof-of-concept in pre-clinical studies is critical. Richard’s point on the target product profile is also important.  There must be an objective addressing an unmet need for patients. Investors also place significant value on the track record of the scientific team.

Richard: Yes, investors will definitely be looking for a proven delivery team plus a clear development plan, how much everything will cost and strategy for payer acceptability. These days, it is rare for a single developer, especially small biotech, to be able to cover all bases to take a product single-handedly through to market. Development typically follows the model of a central sponsor with this linked to robust outsourced partners for e.g. non-clinical, CMC, clinical deliverables.  Cell and gene therapies also necessitate regulatory application of a risk-based approach due to their specific biological nature and inherent complexity of parts. 

What are common blind spots for emerging biotech or academic developers who have small teams for gene therapies?

Jonca: Academic developers need to have a solid understanding of the pre-clinical requirements necessary to advance into the clinic, which can be daunting in scope and expense. Taking advantage of opportunities to get feedback from regulators, like the FDA INTERACT and pre-IND meetings, can be extremely helpful in planning appropriately.

Richard: The biggest blind-spot is being able to transition and adopt a realistic understanding of the time, resources and cost it takes to develop a complex biologic; plus the multitude of moving parts in terms of the product development and GMP production; plus the specific clinical study planning, logistics and execution; also in meeting specific regulatory expectation for this product class. 

How do developers determine what countries should be considered for the early phase study of a cell and gene therapy product and what are the timelines to consider across various countries and/or regions?

Jonca:  An understanding of regional requirements to initiate studies is critical. Developers are often faced with differing requirements that must be built into the clinical development program if a timely global launch in multiple markets is to be achieved.

Richard: Choosing countries or regions needs to be decided in accordance with several factors: the nature of the product; its stability and associated logistics (i.e. certain cell-based products); location of the patient-specific product manufacture and coordination with specialist clinical sites; plus if the product (GMO)/trial is required to be operated under contained or non-contained use. This often needs to be considered case by case and is dependent on the various cross-range and nuances of cell and gene therapies. The time taken for GMO assessment will vary in certain countries and will need to be considered as a pre-requisite.

Duu-Gong: In my opinion, filing a Phase I IND in the United States or Europe may be the best way to initiate the development program.  Since there are various products currently approved in the U.S. and Europe, FDA and EMA have adequate experience to guide the developer in early phase via the pre-IND process to avoid mistakes.  There have been instances where developers have conducted studies in APAC countries and came to the US to seek the FDA’s approval of plans for Phases II and III that resulted in rejection by FDA.

What does a typical timeline look like for early stage regulatory approval for cell and gene therapies? Are there special regulatory considerations or past regulatory precedence to take into account for these types of products?

Jonca:  There is no typical timeline, at least not yet. What is exciting is that these products are addressing diseases in unprecedented ways, often with the potential of cure. Consider, however, that Phase I gene therapy trials have both short- and long-term implications in determining the durability of efficacy as well as long term safety.

Richard: The core development time is similar to normal biologics, however, there are some key factors that need to be taken into consideration. The biggest one of these is GMO assessment. This is required for many regulatory jurisdictions and can take up to several weeks to several months to pass review, dependent on the country/territory. It is mandatory to conduct the trial, therefore needs to be incorporated into the planning.