Adapting learnings to advance CGT clinical manufacturing
By AmerisourceBergen
An expert panel came together at Cencora’s ThinkLive Gene Therapy Summit 2024 during a session titled, “Leveraging past learnings for future-focused solutions to clinical manufacturing.” Led by moderator Christian K. Schneider, M.D., Vice President and Head of BioPharma Excellence, Cencora PharmaLex, leaders from industry and former regulators discussed their experiences with Chemistry, Manufacturing, and Controls (CMC) and clinical manufacturing during early and late-stage development of cell and gene therapies.
Early manufacturing takeaways
One of the first decisions CGT innovators must confront is how they will manage manufacturing of their clinical product. Is it better to work with a contract development and manufacturing organization (CDMO) or make your own product?
“If you work with a CDMO you can leverage their platforms, technologies, and knowledge, but you have to manage the CDMO’s performance, and you are often competing for a slot,” Tamara said. “However, performing your own manufacturing is very expensive.”
With this in mind, Editas Medicine has employed a ‘hoteling’ model, using a partner’s infrastructure for cleanroom management and Editas’ personnel, equipment, and processes for testing and manufacturing for autologous cell therapy and leveraging CDMOs for more established parts of the modality.
“It’s about flexibility and understanding your supply chain and how you're going to be able to navigate that to be able to provide material as you move forward,” Tamara explained.
Regardless of the model, developers must decide how best to navigate CMC and manufacturing risk. In addition to following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on quality risk management (ICH Q9)iii, FCDI adopts stage appropriate risk management.
“At early stages, you’re drawing on your scientific knowledge and looking at the literature to try to identify the risks you need to address and come up with ways to reduce or mitigate those risks,” Christopher said. “In the early stages there’s a much lower bar for potency because the focus there is on safety. Developing a risk assessment strategy early will help when validating and reviewing your process and your assays.”
Tamara emphasized the importance of understanding the mechanism of action (MOA) when developing the analytics needed to assess potency. “Really understand your target product profile and the analytics that you need and how you’re going to develop the relevant potency assays,” she said.
She noted that companies need those analytics to support their registrational study, to interpret early results, and to support any changes to manufacturing facilities or processes during clinical development. This is especially important if you are looking at accelerated pathways to approval as you need established potency assays with acceptance criteria for registrational studies, so you need to start work on potency assays early.
Insight from the regulators
While it is difficult to establish the specifics early on, regulators have taken steps to assist CGT developers with recommendations on appropriate CMC information to submit and guidance on risk-based approaches to CGT manufacturing. The U.S. Food and Drug Administration (FDA), for example, has issued several guidance documents to assist CGT companies with product development, including CMC-related support and draft guidance on potency assuranceiv.
In addition, the agency has conducted townhall meetings where sponsors can submit questions for considerationv. Collectively, these actions provide sponsors with greater clarity on the FDA’s thinking on these topics, Lisa said.
She noted several helpful clarifications in the recent guidance document on human gene therapy productsvi, including:
- Clarifying the term ‘therapeutic editing threshold’ as the degree of genomic modification needed for therapeutic effect
- Commitment to consider the accelerated approval pathway for genome-edited drug products when appropriate data are available
- Clarifying the definitions and testing requirements around gene editing components. For example, when administered in vivo, the genome editing components are defined as drug substances, whereas for ex vivo editing products, these elements are viewed as critical components
Europe has also been taking steps to help streamline and standardize gene and cell therapy clinical development, including draft guidance on quality, nonclinical and clinical requirements for Advanced Therapy Medicinal Products (ATMPs), which was open for public consultation until the end of May 2024vii. As several points from this draft guidance may vary from CMC recommendation required by the FDA, reviewing the new European Medicines Agency (EMA) document early in development may be prudent when launching the drug in Europe.
Dan noted that the United Kingdom’s (UK’s)Medicines and Healthcare products Regulatory Agency (MHRA) recently updated its ATMP webpageviii, including comprehensive resources for regenerative medicines.
“This is really important if your starting material involves either tissues or cells because MHRA are not the only regulator involved,” Dan said. “For example, you may need to contact the Human Tissue Authorityix or the Human Fertilization and Embryology Authority (HEFA)x. Being able to streamline interactions through a one-stop-shop is important for companies developing products otherwise they would have to navigate quite a complex regulatory framework.”
As Christian noted during the discussion, regulators are crossing over from being gatekeepers to being enablers and are offering guidelines while allowing a certain degree of flexibility.
“Platform approaches are not easy, so it comes back to increased communication between developers and regulators to discuss any proposed approaches,” Lisa said.
Given how fast moving the field of CGTs is, another big consideration for industry is regulatory science. “Watch what your regulator is doing in terms of standards and requirements,” Dan said.
Another issue is how to regulate products for small numbers of patients, particularly with ultra rare mutations. One program that seeks to address this challenge is the Rare Therapies Launch Pad, which is focused on a more sustainable and scalable approach to delivering individualized treatments to children with rare conditions, including creating a proportionate regulatory pathwayxi.
“Many ATMPs are developed in small populations and that adds to the difficulty in terms of evidence generation. It’s therefore important to maximize the use of regulatory incentives and opportunities such as orphan drug designation and expedited pathways such as FDA’s breakthrough designation, PRIME at the EMA, and the Innovative Licensing and Access Pathway (ILAP) at the MHRA,” Dan added.
Another challenge is regulatory differences between jurisdictions, such as the EMA and FDA.
“The EU looks at facilities differently from the U.S.,” Tamara said. “In Europe, you have to have Good Manufacturing Practice (GMP) licensure for facilities even in early clinical trials and Qualified Person (QP) release is different from the U.S., so you need to navigate for those.”
Two-way communication
In such a complex and rapidly changing environment, collaboration and a willingness to share knowledge between industry and regulators is crucial. As experts on the panel shared, there is enormous willingness on the part of the regulators to work with industry to find the best way to bring CGTs to market safely.
“Regulators are counting on the scientists and companies to come up with the best way to address development challenges,” Christopher said. For example, he noted that there was concern that CBER would reject FCDI’s methods for detecting residual stem cells in Drug Product using novel mRNA targets identified using bioinformatics , which diverged from the standard pluripotency genes used as targets. “But they saw the data, they realized the power of the approach and that it was an improvement and accepted it, and the approach is now being adopted by others in the field.”
While the knowledge and experience from companies is invaluable to informing regulatory approaches, it is also vital that companies seek out the expertise of the regulators through scientific advice – not only for regulatory approval but to support market access.
With the EU’s new Health Technology Assessment (HTA) Regulation coming into full effect in 2025xii, obtaining joint scientific advice from regulators and payers will become crucial, Dan noted.
“When you’re thinking about evidence generation, it needs to be considered in a holistic way with consideration for what regulators and HTA bodies need in terms of data for their decision-making,” he said. “There are mechanisms to do this at EMA through the Scientific Advice Working Party. In the UK, you can request joint scientific advice meetings between the MHRA and National Institute for Health and Care Excellence (NICE).”
He added that timing with these types of engagements is crucial. “If you go too early, you don’t have sufficient clinical data to base your assumptions with regards to likely effect; if you go too late, and you’ve already started your confirmatory study and the regulators or payers don’t like your approach, that’s a big ask to correct it to achieve regulatory compliance.”
While the U.S. payer market is very different, there are ways to gain insights. Lisa noted that it is beneficial to explore quality of life measures that may be important in the future to payers, or health economic measures, such as hospital utilization, in early clinical trials.
“A consideration in the U.S. market in early development is thinking about the potential payer makeup for your population. Are the majority of your target patients on Medicaid, for example, or are they going to be in private insurance? If state level Medicaid groups are going to be a key payer for your population, sponsors can engage quite early with Medicaid directors, perhaps to discuss the disease burden to their state healthcare systems. Once you have clinical data, come back to further discuss the potential for your product to reduce or offset these healthcare costs.
“With private insurance, I’m aware that sponsors often organize payer ad boards, for example, with insurance companies to understand their perspective and what evidence they're going to need to see from your clinical program,” she added.
Another key stakeholder in the U.S. is the Institute for Clinical and Economic Review (ICER), which performs evidence-based cost benefit assessments, which they seek to complete around the time of anticipated FDA approval for a product.
“Their review process does offer opportunities for sponsors and other stakeholders to engage in the process and comment on their draft assessment,” Lisa noted.
The panelists agreed that more guidance and feedback to sponsors, particularly on how regulators view platform approaches, would be helpful, as would greater harmonization between the regions. Following Cencora’s ThinkLive Gene Therapy Summit 2024, the FDA published the draft guidance on Platform Technology Designation Program for Drug Development, including widespread attention in the communityxiii. More informal feedback, perhaps through quick touchpoints, would also help with troubleshooting and being able to get a sense of where the regulators stand on key issues.
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