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In Draft Guidance for Cell and Gene Therapy Industry, FDA Broadens its Approach to Product Potency

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NEW YORK – In the last days of 2023, the US Food and Drug Administration put out a draft guidance meant to better support drugmakers' efforts to bring novel cell and gene therapies to market.

If the 25-page draft document of nonbinding recommendations, titled "Potency Assurance for Cellular and Gene Therapy Products," is finalized, it will replace the agency's 2011 guidance on potency testing for such products.

The FDA's latest draft guidance comes as drugmakers developing novel cell and gene therapies — bespoke products manufactured for each individual patient — have increasingly expressed confusion about what exactly they need to do to show regulators that they can reliably and consistently produce each dose and batch of these treatments so they work as intended. This is what the FDA refers to as a cell and gene therapy product's potency — "the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result." Just like ensuring a product's sterility, ensuring a product's potency is paramount to getting it approved for commercial use.

But unlike small-molecule drugs and more traditional biologics that drugmakers produce in batches, making multiple doses using the same ingredients, one dose of a novel cell or gene therapy customized for a patient can differ in important ways from another dose made for another patient. Measuring the potency of these novel, bespoke products, therefore — let alone identifying, developing, and administering a test that can measure these parameters — has been a significant barrier to bringing these therapies to market.

"This is a very complex and ongoing challenge, given that there are so many variables to determining what attributes have potency in cell and gene therapy," said Bambi Grilley, director of clinical research and early product development at the Baylor College of Medicine's Center of Cell and Gene Therapy and the chief regulatory officer at the International Society for Cell & Gene Therapy (ISCT).

The FDA recognizes this challenge and has been intent on advancing a more workable framework for evaluating product potency for cell and gene therapies. The agency has, for instance, offered as many one-on-one meetings with companies as its staff can accommodate, and has been open to "potency matrix" strategies, where sponsors can use an amalgamation of several potency assays instead of just one potency assay, as was more common in traditional small-molecule drug development.

Even with matrix strategies, however, drugmakers have struggled to define their products' potencies and have pushed the FDA for clarity on the types of potency measurements it will and won't accept in regulatory applications.

The agency released the new draft guidance in response to these requests, according to Matthew Klinker, chief of one of the cell therapy branches at the Office of Cellular Therapy and Human Tissues within the FDA's biologics division. "The [cell and gene therapy] field has seen significant progress since 2011, and we've certainly learned a lot since the publication of that [2011 potency assay guidance document]," he said in an explanatory webinar released alongside the draft guidance. According to Klinker, the document effectively replaces the potency assay approach detailed in 2011 with a broader approach called a "potency assurance strategy."

The approach proposed in the draft guidance isn't meant to further burden drugmakers with additional requirements when it comes to defining and measuring product potency, he explained. "While the new approach is certainly broader, it's also more flexible," he said. "If there are limitations in one aspect of your potency assurance strategy, other aspects of the strategy may be able to compensate for those limitations."

For instance, some drugmakers may struggle to identify what precisely defines their product. This is especially true of products made from patients' own cells. These products may be difficult to measure consistently since so much of the "product" is the process used to harvest the cells, expand them, store them, and readminister them, as opposed to the "product" being those cells themselves. In these cases, other aspects of a potency assurance strategy could play a more important role than lot-testing the product with a given potency assay.

"A potency assurance strategy is a comprehensive approach to help ensure that every lot of a product will have the potency necessary to achieve the intended therapeutic effect," he said. "This broader approach is one of the main differences between this draft guidance and our 2011 potency guidance, as our 2011 guidance focused almost entirely on potency tests for [cell and gene therapy] products."

The new potency assurance strategy is more focused on minimizing anything that could affect a product's potency and less on measuring that potency with a specific test or series of tests.

Mirroring the existing sterility approach

Recognizing that this change could be tough to conceptualize without a concrete example, Klinker compared it to the agency's existing approach for measuring product sterility.

The way the FDA requires a product to be consistently sterile involves steps beyond simply testing the product, he said. These steps include designing the facility where the product is manufactured to make sure it is appropriately controlled for sterility and implementing monitoring protocols to make sure the environment is sterile, too. Controlling the sterility of the materials used to make these products, like reagents and consumables, and ensuring they don't introduce microbial contaminants to the manufacturing process is also a big part of the sterility assurance framework. Finally, conducting simulations to make sure the process is consistently sterile can also reduce the risk of introducing anything that could compromise the product's sterility.

Even though all these strategies are part of the overarching approach to ensuring product sterility, a final test on the product is still necessary, Klinker added. But that final test isn't the be-all and end-all when it comes to sterility assurance.

"The key point I'm trying to make is that testing a product for sterility is not what makes it sterile," he said. But rather, "the sterility of the product is ensured by taking a broader approach to reduce the risk of contamination to an acceptable level, and the role of the sterility test is to confirm that the overall strategy for mitigating the contamination risk has worked as intended."

The potency assurance strategy, in many ways, mirrors the sterility approach, Klinker continued. In the draft guidance, the FDA recommends that a drugmaker first identify which attributes or characteristics of their product are necessary for potency. Then, the drugmaker should develop what the agency calls a "quality target product profile," or QTPP, based on these attributes.

The QTPP should consider not just the product's mechanism of action, but also how it applies to the product's specific indication and the exact way that the drugmaker plans to administer the product.

After identifying the QTPP, the drugmaker should home in on potency-related critical quality attributes, or CQAs, that are necessary for the drug to have its intended therapeutic effect. Importantly, Klinker pointed out that CQAs could cover a broad range of attributes, not just those that a drugmaker might typically think of in terms of targets for measuring potency.

"Therapeutically relevant biological activities, such as those traditionally measured with potency bioassays, are certainly considered potency-related CQAs," he said. "But physical aspects important for the intended therapeutic effects would also be considered potency-related CQAs."

Mitigating risks

After a drugmaker identifies their product's potency-related CQAs, the agency recommends conducting a risk assessment for each one of them and determining anything that could compromise the CQAs.

These risks could arise in the manufacturing stage, but they could also come into play once the product is released from its manufacturing environment to be administered to a patient. Klinker provided the example of a container closure for a product, which could affect the product itself, as could the devices and procedures that are used to administer the product and the storage and shipping conditions used.

The drugmaker should not only identify these risks but also determine the likelihood of each risk occurring, as well as how severely it would affect a product's potency should it occur. Subsequently, the drugmaker should design mitigation steps for these risks. 

"In this guidance, we recommend a broad, multifaceted approach to mitigating risk to product potency," Klinker said. "Potency tests have an important role in this approach, but testing the product is not what makes it potent."

Instead, he said, "the cornerstone of an effective potency assurance strategy is a well-designed manufacturing process." And if any variability in the material used to manufacture a product could affect its potency, the drugmaker should control these attributes of the material, too, the FDA recommends in the guidance.

Klinker offered an example of this. If a cell or gene therapy uses a recombinant protein to stimulate cells and induce a specific phenotype of that cell that would be important for the therapeutic effect, then the drugmaker should control for the biological activity of that recombinant protein so as to reduce the risk of that protein affecting the product's overall potency.

Certain parameters, like the time in culture, could affect a cell therapy product's potency, too, he noted, and the FDA therefore recommends that drugmakers identify critical process parameters with appropriate limits and ranges to mitigate risks to potency.

Finally, once all of these risk mitigation measures are in place, the drugmaker should have at least one physiochemical assay or bioassay that measures an activity related to the intended therapeutic effect of the product.

"The assay should be precise, accurate, specific, and robust," Klinker said, adding again that the role of a test like this performed on a lot of a product is just one part of the overall assurance strategy. Not every potency-related CQA needs to be tested for lot release, he noted. Instead, this is only necessary for those CQAs that a drugmaker has identified as being at risk.

"It's typically not feasible to reduce risk to all potency-related CQAs to an acceptable level through these other aspects alone," he said. "Therefore, potency assurance strategies should usually include multiple release assays, and in most cases, these assays should include at least one bioassay that measures a product activity that is relevant to its intended therapeutic effect."

Life cycle of a potency assurance strategy

Another key point the FDA emphasizes in its draft guidance is that a potency assurance strategy should evolve throughout a product's clinical development as a drugmaker gains manufacturing experience and clinical data. Although the FDA does recommend that a developer define its potency assurance strategy from the onset, Klinker acknowledged that "some aspects of your strategy may not be fully mature during the early stages of development."

A potency assurance strategy can be fluid in the sense that it gets better over time, as a drugmaker learns more about its product and manufacturing process, he said.

"As you progress through product development, you should routinely reassess and refine your potency assurance strategy as necessary," he added.

In an investigational new drug (IND) application for a given cell or gene therapy candidate, the FDA tells sponsors to describe the intended strategy for potency assurance, including the chemistry, manufacturing, and control information that they plan to use to assure the proper identification, quality, purity, and strength of the investigational therapy.

"Your IND submission should include a summary of your current potency assurance strategy as well as some information on how you plan to collect the necessary data to refine your current strategy during the product development," Klinker said, adding that the description should include an explanation of what the drugmaker understands to be the product's mechanism of action and its QTPP as well as a list of the potency-related CQAs for the product. The drugmaker should also walk through the rationale for its proposed potency assurance strategy, identifying the risks and mitigation steps.

One-on-one feedback

Even though the FDA published the draft guidance to support cell and gene therapy developers, the agency also acknowledged that the outcome of these potency assurance strategies — just like the therapies they concern — are, by nature, unique. "We are well aware of how challenging it can be to control the potency of [cell and gene therapy] products, and we know that clear communication between the FDA and individual developers is critical to meeting these challenges and avoiding delays in development," Klinker said. 

For this reason, the agency also recommends in the draft document that drugmakers engage with the Center for Biologics Evaluation and Research early in the life cycle of their products and ask specific questions about the potency assurance strategy during meetings or via an IND amendment. FDA reviewers at CBER will only be able to answer questions during a meeting if those questions have been included in the briefing materials, the draft guidance notes.

Although the FDA's guidances are not legally binding even after they're finalized, they do represent the agency's thinking on regulatory matters and heavily influence industry activities.

Industry players still have more than two months to comment on the draft guidance. ISCT, for instance, whose membership includes clinicians and industry players in the cell and gene therapy space, plans to submit official comments to the FDA toward the end of March. 

Some have already commented. In the Federal Register, Asymmetrex, a firm that markets tests to quantify cell subtypes in stem cell products, has commented publicly that the draft guidance is "greatly deficient for crucial considerations for actual cell therapy products … which are characteristically and invariably cell-[heterogeneous]."

Asymmetrex, as a seller of the types of tests drugmakers use to measure the potency of their cell and gene therapies, has a stake in the game. But the firm's overarching complaint — that the draft guidance isn't clear enough on specific technologies for testing cell products — hints at the fact that this latest FDA guidance is unlikely to dissipate all of the regulatory challenges in the fast-moving cell and gene therapy space.

"Some minor areas [of the guidance] need further clarification," ISCT's Grilley echoed. "For example, more specific details are needed on the requirements for potency assays for Phase I, which will be of particular benefit to those submitting an IND for FDA review."

Still, the fact that the FDA is putting out guidance in the first place comes as welcome news for an industry seeking more transparency on cell and gene therapy regulatory requirements.

"ISCT sees this draft guidance document as a valued effort from the FDA to help developers define their potency assays," Grilley said. "The draft document includes detailed information about the FDA's expectations for cell and gene therapy products to reach approval, which will prove very useful for developers in the field."