The annual meeting of the International Society for Cell & Gene Therapy (ISCT), held last month in San Francisco, zoned in on that hurdle.
A roundtable discussion, Potency Assays: Why, When and What If?, looked at how to bridge clinical data, remove variability, and assess alternate applications of potency assays during development and manufacturing:
Indeed, the US Food and Drug Administration (FDA) has stressed the importance of using a validated potency assay before Phase 3 trials for CAR-T cell therapies.
There have been a number of companies that have stumbled in relation to this area in their submissions to the FDA, to the European Medicines Agency (EMA) and other agencies; the potency assays they used may or may not have been appropriate, according to ISCT 2022 president, Bruce Levine, who is also professor of cancer gene therapy at the University of Pennsylvania.
“The agency won't tell you what potency assay to run, just that the assay that you run has to have some correlation to activity,” he told us.
In standard drug development, the ideal potency assay is one that is simple, fast, cheap, and repeatable.
In terms of cell therapies and gene modified cell therapies, these are very different types of drugs: “We manufacture ex vivo, that product is probably still changing. And as you infuse the cells, [back into the patient], they may change [their properties] in response to their environment.”
Therefore, it is challenging to think about potency in the conventional sense with these kinds of therapies, he said.
Dialogue is key
“But it is something we are working through. And that is where the real value of the ISCT meeting comes into play, especially in person, and particularly with stakeholders from the regulatory agencies present so that we can engage in that dialogue," continued Levine.
That type of forum for exchange can serve to deepen the knowledge of the staff at the regulatory agencies, who may not have seen a new technology or some new type of gene editing before, he added. “They themselves are recruiting and training people who are new to the regulatory environment, and cell and gene therapies. So it works in multiple ways.”
Collaboration and regulatory harmonization, on a global level, is essential in relation to finding answers to a lot of the challenges related to the cell and gene therapy (CGT) space, said Levine.
The ISCT has relationships around the world with bodies such as the Therapeutic Goods Administration (TGA) in Australia and the World Health Organization (WHO), among others.
“We need to continue to engage with the regulatory agencies and staff, and they want to be engaged, they want to learn, they want to hear from us, and we need to hear from them,” said Levine.
Also top of mind at the ISCT 2022 meeting in San Francisco, the organization’s first in person event since Melbourne in 2019, was the need for CGT workforce education and training given the "talent shortage" that exists because of the rapid growth of the industry.
“We have been extraordinarily successful in our early stage mentoring program - that's been growing by 50% year on year," noted Levine.
The organization is looking to other sectors as well, pulling in talent from different fields and from companies developing other types of biologics such as monoclonal antibodies and proteins in an effort to attract people at the more mid-career level to the CGT space, he explained.
“We have also been running an educational program in this respect – workforce development in biomanufacturing - in partnership with the National Science Foundation (NSF) funded Engineering Research Center for Cell Manufacturing Technologies (CMaT) led by the Georgia Institute of Technology.”
Developed by field experts from academia, regulatory, clinical, and commercial domains, that program is designed to upskill key personnel for roles within companies and clinical manufacturing centers across the CGT sector, said Levine.
The spotlight was also on rare genetic diseases at ISCT 2022.
In a roundtable session hosted by Levine, panelists debated the dilemma of rare genetic diseases, and the challenge of making CGTs for these commercially viable. The idea of organizing an academic, not for profit consortium to support this kind of research and development work was muted. “It was a thought-provoking and inspiring discussion.”
Sven Kili, ISCT 2022 co-chair and CEO of the Swiss-based biotechnology company, Antion Bioscience, looking at some of the CGT manufacturing challenges highlighted at the meeting, said one area of particular focus was the scaling of autologous therapies, and the existing hurdles in relation to that, linked not only to cost, but also to manufacturing space and capacities.
“The growth in allogeneic therapies is helping to alleviate some of these challenges, but we are unlikely to move completely away from autologous therapies. For therapies that will remain autologous, there is a lot of work ongoing to explore manufacturing mechanisms that minimize human manipulation and so limit risks and speed up the process. This is already being seen with certain companies talking about being able to manufacture autologous CAR-T cell therapies in three days.
“Additional challenges relate to defining appropriate critical quality attributes (CQAs) for therapies and how we get better at this and then think about using them to assist in defining viable and appropriate release assays and criteria.”
Another ISCT 2022 roundtable session, which Kili chaired, asked whether CGTs are a first world only luxury.
“It included speakers from Africa, South America, India, as well as the US, all bringing their perspectives as clinicians, scientists, researchers, therapy developers and NGO representatives to the topic.
“What became clear is that each country has their own unique challenges and we need to be very careful about putting all lower and middle income countries in the same basket.
“There were some very engaged discussions on the need to educate local payers and regulators and the importance of being able to show not only clinical efficacy but also value generated by a therapy, that it can have a bearing on the wider population and economic system.”
The panel also explored various mechanisms to encourage investment in their locations to develop and grow the CGT sector, he said.