How to Maximize the Value of Cell and Gene Therapy Products: 5 Tips for Success

This article has been updated since its original publication date.

Product development is an extremely time consuming and challenging process for any pharmaceutical, biotechnology, or medical device, but when it comes to cell and gene therapy products, the process requirements change significantly from existing treatments. Now you may be wondering: why are cell and gene therapies so challenging to develop? Cell and gene therapy product development is challenging because the science behind these products has advanced so far ahead of the regulations and the technology being developed. It is important to note that the regulatory agencies have highly skilled professionals, but the bureaucracy and regulatory nature of government’s role requires time for evaluation, consolidation, consideration, and holistic oversight.

How can you overcome this struggle and bridge the knowledge gap that is being created by the lagging regulations? Here are five tips that will help you maximize the value of your cell and gene therapy product, these include:

1. Building an effective Quality Management System (QMS) for your evolving product
2. Ensuring your nonclinical program and your regulatory goals are aligned
3. Meeting with the regulators as early as possible
4. Engaging the regulators as partners
5. Being aware of common failure points

#1: Building an effective QMS for your evolving product

Ensuring you have an effective QMS begins during early-stage product development and extends throughout the entire lifecycle of a product. It is critical that you maintain an effective and compliant QMS at all times. Having an effective quality management system in place will allow you to provide your product with support in a number of ways including product characterization, development, and specification.

At the end of the day, one of the most important aspects of cell and gene therapy product development is product quality. Having an effective QMS brings quality into the product through:

• Improved management
• Effective use of resources
• Improved and customized processes
• Continuous improvement
• Improved consistency and compliance
• High-quality products
• Lower costs

#2: Ensuring your nonclinical program and your regulatory goals are aligned

Cellular therapy products are a form of medical treatment that uses cells or tissues to treat or prevent a disease. It involves the transfer of cells between individuals, either from the same person (autologous) or from a different person (allogeneic). Potential safety concerns associated with cell therapy products include risk of delivery procedure, ex-vivo manipulation, potential inflammatory/immune system response, inappropriate proliferation or cell differentiation, or cell migration to non-target issues.

As stated by the Food and Drug Administration (FDA), "human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use." Potential safety concerns include risk of delivery procedure, type of vector/virus, vector/virus biodistribution to non-target tissues, level of viral replication and persistence in non-target tissues, inappropriate immune activation, potential for insertional mutagenesis and/or oncogenicity, and transgene related concerns.

In 2013, the FDA issued a guidance document stating that these are novel therapies, which means they should also have novel testing paradigms and not a "one size fits all" nonclinical program. As such, the manufacturing process of the cellular product used in the nonclinical studies should be as similar to the intended clinical product as possible (can use analogous cellular product but is not optimal).

Sponsors should also take great caution when looking into the nonclinical animal model considerations and evaluating the various types of studies to ensure that the studies conducted align with their overall regulatory goals and strategy. This means identification of effective models to establish toxicity, routes of administration, and safety.

#3: Meeting with the regulators as early as possible

In 2018, the FDA introduced a program called INTERACT (INitial Targeted Engagement for Regulatory Advice for CBER ProducTs), which formalized the meetings previously referred to as pre-pre-IND (ppIND) meetings. INTERACT meetings allow Sponsors to gain FDA input at a very early stage of product development. The meetings are focused primarily on nonclinical testing, but input on chemistry, manufacturing, and controls (CMC) and clinical aspects of development programs can also be obtained at this time. These meetings are non-binding, informal scientific discussions between FDA and the Sponsor at an early stage of development but are not intended to take the place of a pre-IND meeting, which occurs prior to the submission of an IND to discuss the development plan, including all conducted and planned nonclinical studies and if they are going to be acceptable to the FDA. Product approval data bears this statement out by showing that most, if not all, approved cell and gene products adopted early regulator meetings.

#4: Engaging the regulators as partners

The culture of each Sponsor company varies greatly, and it is these different corporate cultures that can shape the relationship that the Sponsor forms with the regulatory agencies. On one end of the spectrum, you have the companies that take an extremely cautious and secretive approach, only disclosing the information specifically asked for by the FDA and/or the European Medicines Agency (EMA) and local national agencies. While on the other end of the spectrum you have Sponsors who take a more confident and combative approach, acting as though they are better than everyone else and like they need to educate the agency. And then somewhere in the middle, you have the companies who take an open and collaborative approach to interacting with the regulators, going in with the attitude that both parties can work together to shape the development of their product. This is the best approach to take when engaging with the regulatory agencies, and the one that is taken by almost all Sponsors who achieve successful interactions with the regulators.

As mentioned above, one of the major factors that makes cell and gene product development more challenging and difficult is the fact that the products are so far ahead of their time and the regulations have not yet caught up. In addition to that, there are not many precedents to follow when compiling a Biologics License Application (BLA) and/or a Marketing Authorization Application (MAA), adding to the challenges that are faced by many during the approval process. Because of the way this landscape looks currently, it is even more important for Sponsors to not only engage with the agencies early and as frequently as possible, but to do so in the most collaborative way possible. Working with the regulators to form a sort of partnership is the surest way to achieve success for your cell and gene therapy product.

#5: Be aware of common failure points

There are many failure points that Sponsors may find themselves in throughout the product development lifecycle of cell and gene therapy products. The five most common failure points include:

1. Data integrity issues
2. Failing to have a full understanding of the patient population
3. Lack of a clear roadmap to the next milestone
4. Not employing QMS soon enough
5. Lack of competent sponsorship

Simply being aware of what these failure points are will allow Sponsors to take the necessary steps to avoid falling victim to these issues. However, if you do find yourself in the trenches of one of these pitfalls, the experts from ProPharma’s Cell and Gene Therapy Center of Excellence can help you correct your mistakes and take the necessary actions to course correct and get back on the appropriate track to reach the next regulatory milestone for your product.