If even the most conservative projections are believed, the number of product approvals in the cell and gene (C&G) therapies space will grow geometrically over the next few years. One estimate of the cell and gene pipeline has more than 200 products being developed, across almost every conceivable therapeutic area, by 40+ companies. To state the mathematically obvious, most of these companies are not top-ten biopharma and the majority are small companies, ranging from startups to mid-size companies with very limited experience of the drug development process and commercialization. This is in sharp contrast to the big picture in even advanced small-molecule development, which has a much greater presence of household name drug companies with their decades of development and manufacturing experience.
One big reason for this modern-day goldrush is that cell and gene therapies offer the promise of huge increases in effectiveness and in some cases, the potential for functional cure. There is great ethical and altruistic value here, with a connection to patients and a desire to help drive a very hard push to achieve the goal of product approval. The result is many smaller companies rightfully moving as fast as possible (and sometimes faster than is practically possible, or at least sustainable) to deliver these unprecedented benefits to patients. This focus on speed, coupled with the practical reality that few people have launched a C&G product so far, means that this path is fraught with risks and challenges.
As VP of the Cell and Gene Therapies Practice with Quality Executive Partners (QxP), a large part of my job is to monitor and stay connected with companies developing products in this space. Looking at this industry through the lens of a trusted advisor’s viewpoint, we are seeing key themes emerge, with influence at each stage of the company’s and product’s lifecycle.
In response to our observations in the C&G space, we are introducing a series of articles that will be published over the remainder of 2023.
This series of articles will discuss some of the most significant themes and issues that we see being faced by companies delivering on the C&G promise in the short and mid-term future. We will go on to provide insight and suggestions on how to clear these hurdles quickly and effectively manage risk for the overall goal of product approval. The series will roughly follow the sequence or life cycle of product development, from startup to commercialization. We will deliberately avoid getting into a lot of technical detail, since such details tend to be product-specific and since there is no shortage of technical and scientific capability in this community. Instead, we will focus on leadership and management processes, strategy, and tactical implementation of what is necessary in order to develop and commercialize a complex Cell- or Gene-Therapy product.
It’s important to note that this series of articles will focus on the key themes that define and differentiate the C&G sector. As such, we will make some very significant assumptions about the more general aspects of operations in the biopharma industry, and we will use a reasonable expectation of baseline capability in biopharma as the starting point for discussion of specific topics. This means that we will assume that any company has:
- The basic management structure, processes, and staff in place to operate in a deliberate, responsible and sustainable manner, with experienced senior leaders guiding the way.
- A cultural and operational commitment to quality. There is an effective, phase-appropriate quality system in place and there are quality professionals on board to manage quality operations. There is a cultural recognition that commitment to developing safe and effective product is essential and that this consideration properly guides all decisions and operations.
- The scientific expertise to develop the product in question, the rigor to record scientific data and the means to store and retrieve those data such that data integrity is preserved.
- Facilities and equipment in place that are suited to the work being performed and are managed according to defined processes to maintain the reliability and availability of function of these assets.
Beyond acknowledging these basic requirements, we will not go deeper into how to make this all work in this series of articles. The key point here is that while sound science and robust technology are essential for the launch of a novel C&G product, they are by no means sufficient, and so it is crucially important that leaders pay full and early attention to each of the points covered in this discussion.
While we will be talking primarily about C&G Therapy companies and products, we should recognize that the issues faced in C&G are in large part the result of considerations and drivers to deliver, instead of the specific advanced science and technology per se. As such, the themes discussed will be most relevant to situations where these drivers are most notable. It is therefore very possible that companies developing products that are not specifically C&G Therapy products, but share some or all key drivers, will benefit from these insights. We will let you, the reader, decide on what is ultimately most useful.
With that, we will be structuring the series of articles based on addressing these key considerations and drivers, which are themselves based on our direct observations of the C&G sector, and perhaps even into the wider areas of complex biopharma. These key drivers include:
1. Investors and Sponsors struggle to build a relationship past their first date.
In 2023, it is becoming increasingly hard to attract and secure investment money. The very large number of companies seeking investment funds, coupled with the large, but limited amount of available investment is creating a competitive environment. There is a very apparent difference between what investment targets and investors see as the key factors leading to a positive decision to invest, resulting in a paucity of well-funded programs and an increasing number of companies at, or on the edge of, financial failure.
2. Making GMP supplies of novel products is hard, and capacity is in short supply.
Manufacturing capability and capacity is heavily constrained. The demand for initial GMP batches leading up to early clinical supply is huge, while available capacity for process development and manufacture at Contract Development and Manufacturing Organizations (CDMOs) is very limited. Additionally, supply of complex starting materials such as plasmids is also heavily constrained. For companies considering building their own manufacturing capability, they face the non-sequitur of having to design a facility to perform a process that is not yet defined. Additionally, manufacturing facilities are expensive (in the hundreds of millions of dollars) and have a very long lead time.
3. Analytical methods lag behind manufacturing but are essential to the product disposition (release) process.
There is a lack of standard analytical methodologies and approaches to set the specifications for novel C&G products. In order to commence clinical trials, a sponsor company must be able to ensure that the product is safe. While the methods used for sterility assurance (sterility, endotoxin, mycoplasma) are well defined, they must still be validated for the product matrix. In addition to sterility assurance measurements, other safety considerations specific to the mode of treatment must be considered from a scientific and ethical point of view. The most notable aspect here is immunogenicity. Further, since clinical efficacy outcomes from the trial must be correlated with measured potency of the product, it is imperative that the sponsor can reliably and accurately measure at least a meaningful surrogate for potency. This typically requires extensive analytical method development.
4. The large number of sponsors currently running clinical trials is exacerbating the existing constraint on clinical trials expertise.
Clinical operations and clinical quality assurance expertise has always been in relatively short supply. A typical startup company developing its first C&G product will likely struggle to establish sufficient expertise and management processes to avoid the potential risks to patient and to trial outcome. Further, a small company seeking the services of a contract clinical research organization (CRO) may not have mature processes in place to select and manage the CRO relationship, and the CRO may see the sponsor company’s business a less important due to its size. However, effective management of clinical trials, including risk management and data integrity, are essential to support an approvable license submission.
5. Accelerated development timelines expose license applications to increased data integrity risk.
Not long ago, a typical biopharma product took a decade or more to go from applied science to license application. These days, a C&G product is making the same journey in perhaps 4 years. This means that Module 3 (i.e. the Chemistry, Manufacturing and Controls) section of the eCommon Technical Document (eCTD), is very likely to include data from early development that would not previously have seen the light of day on a regulator’s desk. These early data are often developed according to working practices and controls that were appropriate for early science but might not meet the data integrity requirements of a submission to a regulator. There have been examples of long delays at submission review and approval because of a lack of confidence in such data, driven by an evident lack of controls for data integrity (even though the data itself is sound). There is therefore substantial risk associated with inadequate management of early development work and the resulting data that if not addressed at the time the work is done, cannot ever be fully corrected after the fact.
6. Scale-up and commercialization present challenges that are different than those encountered earlier in development.
Manufacturing at larger scale, while preserving the quality of and comparability to clinical trial material presents challenges in process science, engineering and logistics. Further, if early work did not adequately define the measures for product quality and the reference standards used as comparators, then this stage can be particularly challenging. Since this work will be going on at the same time as the sponsor company is likely growing rapidly (in preparation for commercial activity) it presents a huge challenge across the company. Without experience navigating this stage, errors are likely to occur at the program management level that can be immediately costly and can cause delays in approval.
7. Pre-approval inspections (PAIs) are where the rubber meets the road (and makes skid marks)
While large sponsor companies will certainly have established processes and deep experience in managing both the daily activity of a PAI and the response to the (almost inevitable) Form 483 observations, smaller sponsor companies may well lack this expertise. It is not unheard of for even senior scientists with little GMP background in a small company to be taken aback by the intensity of a PAI. Observations are very likely, and the right approach to a formal response is essential. Indeed, a well written response can make a huge difference in approvability and the timeline of that approval.
Each of the following articles in this series will address at least one of these key risk drivers in more detail, with the intent of providing insight, suggested path forward and important points to consider. The intent is to provide value to readers from a range of functions and responsibilities within operating companies (i.e. sponsors), as well as people working in supporting organizations providing key services, such as CDMOs and CROs. Additionally, it is intended that this series will provide context for investors to identify, select and guide their investment targets, resulting in both increased return on investment and an improved chance of a successful product development and commercial launch.
The first article will tackle the strategic issue of sponsor companies and investors not being able to jointly establish agreed investment deals. It will focus on what sponsor companies can do to educate and inform investors and the key management process they can establish that makes them much more attractive to early investors.
At QxP, we are veterans of the industry, with strong interest in a robust supply of highly effective medicines being available for patients. As consultants, we work with clients across all aspects of Cell and Gene, biopharma and more conventional pharmaceuticals, with the intent of promoting joint success in delivering safe and effective medicines. The patient is waiting. We hope these articles are interesting and helpful as we go about the important work of helping to improve the lives of patients everywhere.
About the Author
Mark Roache, VP of Cell and Gene Therapies for Quality Executive Partners, Inc. and President of BioQPartners Inc., has spent his entire career working in GXP with more than 30 years of industry experience, from development, through technical operations and quality management. He held the position of Chief Quality Officer for AveXis (now Novartis Gene Therapies) at the time of Zolgensma launch. He was previously Senior VP of Quality for KBI (a CDMO with cell-therapy capabilities) and has held other senior Quality roles at Novartis, Merck and Bayer. He also has extensive experience in vaccines, recombinants and aseptic processes.