Draft guidance on potency assays for CGT products garners extensive stakeholder input

Regulatory background: Product potency and assays

• As defined in statute, the FDA uses the term “potency” to refer to the “specific ability or capability” of a product to “effect a given result.” The regulations also explain that this trait can be demonstrated via appropriate laboratory tests or adequately controlled clinical data. Overall, potency—while critical to product integrity—is just one component which the agency uses to assess product quality, alongside identity, strength and purity. Each of these factors are important because of their potential role in altering the safety or effectiveness of a product.
• How does “potency” apply to cell and gene therapy (CGT) products? This is a question that sponsors have been struggling with for quite some time. While the FDA finalized a guidance on the use of potency assays for CGT products back in 2011, much has changed since then, including the FDA’s review and approval of a few dozen CGT products—experience which the FDA notably lacked at the time the CGT potency guidance was released. As a result, the 2011 guidance was generally seen as basic and outdated. For example, in describing how potency should be demonstrated for CGT products, the 2011 guidance simply stated that potency for gene therapy products is derived from “at least two biological activities for its potency: the ability to transfer a genetic sequence to a cell; and the biological effect of the expressed genetic sequence.”
• Assays are tests designed to assess various properties (like potency) of chemical or biological samples. In drug development, biochemical assays might be used to determine a product’s binding affinity to a target receptor of interest, along with the strength, stability and duration of the target-ligand complex after the product binds to the receptor. Similar experiments can be conducted to determine a product’s potential for off-target binding as well. In addition to assessing binding capabilities, assays can also be used to characterize the activity elicited by a product, whether bound or unbound to the target of interest. For example, assays can help characterize the activity of a drug-protein complex following product binding, and/or to detect whether certain chain reactions occur.
• Not only are assays useful tools for characterizing products early in development; they can also be used to set “benchmarks,” allowing sponsors to verify that the lots of the product used during clinical trials and eventually, for commercial distribution, continue to adhere to the same standards specified in the original product’s design. This ideal version of the original product, intended to be optimal in every way, can be referred to as the design criteria or Quality Target Product Profile (QTPP). In a perfect world, every product manufactured would be an exact replica of the QTPP. In reality, however, even tightly controlled processes cannot predict and prevent every potential issue that could arise during the manufacturing process. Furthermore, the more complex the manufacturing process, the greater the likelihood that a small deviation in the process will occur.
• As a product is refined during development and/or as additional properties about a product are discovered, more sophisticated tools are required to better understand its impact on cellular processes and systems within the body. Cell-based assays, while more complex to develop and use, offer another option for characterizing product activity at a slightly higher level, allowing sponsors to measure the further downstream effects of products (e.g., morphological cell changes or alterations in protein production or expression). For therapeutic protein products, a critical use of assays is the detection and assessment of potential anti-drug antibody (ADA) formation, signaling a product’s potential to induce an unwanted immune response.

Potency assays for cell and gene therapies: The newest guidance

• At the very end of 2023, the FDA released a draft guidance on establishing CGT product potency to replace its previous 2011 version. That 2011 version walked sponsors through the steps of selecting, qualifying, validating and submitting information to the FDA on potency assays used to measure important characteristics of CGT products. In contrast, the new revised draft downplays the role of potency assays in product development and focuses heavily on the need for sponsors to develop holistic quality control strategies. Even though many of the specific recommendations from the 2011 guidance have been carried over from the previous version, the document reads quite differently. In its Federal Register announcement for the document, the agency stated that the updated guidance includes recommendations which are “necessarily general” due to the “diversity of CGT products and the product-specific nature of potency assays.” [ See AgencyIQ’s in-depth analysis of the draft guidance here.]
• In an effort to further explain its current views on potency assurance, the FDA also recorded a webinar to accompany the new draft. In the recording, MATTHEW KLINKER, Chief of OTP’s Cell Therapy Branch 2, walks through the contents of the guidance and explains how it differs from the previous version. In describing the rationale for the FDA’s shift in approach, Klinker used sterility assurance as a parallel example, explaining that, “Testing a product for sterility is not what makes it sterile—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 FDA’s revamp of the potency assay guidance extends these same principles to this other important aspect of product development, he emphasized.
• What does progressive implementation of a potency assurance strategy mean? In the webinar, Klinker stated that sponsors should already have some type of potency assurance strategy in place, if “not fully mature,” by the time that an investigational new drug (IND) application is submitted. An early-stage strategy should include “identification of initial potency-related critical quality attributes (CQAs) for the product, an assessment of risks to potency-related CQAs, and measures to mitigate these risks.” In line with this advice, he stated that the following items should be submitted to the FDA with the IND: information regarding the product’s mechanism of action and QTPP, a list of initial potency-related CQAs plus an explanation of how they were identified, and a description and justification of the potency assurance strategy. By later stages, the agency expects sponsors’ strategies to be refined, with at least “one assay measuring a potency-related CQA with appropriate acceptance criteria.”
• The new draft guidance can be broken into three main parts. The first (pages 1-5) explains what regenerative medicine products are, provides an overview of what “risk management” means, and cites the requirements that drug developers must satisfy per the U.S. Code in order to have their products approved by the FDA. It also tees up the relationship between potency, product quality and risk management, explaining that “Risks are factors that may adversely affect product quality, including product potency. Sources of risk to the potency of a product include, but are not limited to, inadequately designed or poorly controlled manufacturing processes, variable materials, and undetected changes in the potency-related attributes of the product.”
• The second section of the guidance (pages 6-14) reads as an abridged version of the ICH Q9(R1) Guideline: Quality Risk Management, adapted specifically to CGT products. In opening, the section explains that the “foundation of an effective potency assurance strategy is a manufacturing process that is designed to consistently produce a potent product.” In other words, rather than just focusing on potency assays – which might be described as a downstream measure to prevent the release of unfit products to patients – the guidance endorses the use of upstream solutions to ensure product quality as well. For instance, it states that aspects of manufacturing which may affect potency should be controlled, including “material quality, control or monitoring of manufacturing process parameters, and in-process testing.”
• Section three of the guidance (pages 18-27) describes the considerations for potency assay selection and the criteria that sponsors should use to determine whether an assay is fit-for-purpose. Basically, just like any other tool used in scientific experiments, the guidance explains that assays should be used in the proper context. Assays should be precise, accurate, specific and robust so as to mitigate risks to potency-related CQAs. Also, if an assay is designed to measure a specific aspect of a chemical or cellular process, it should be used accordingly, within that scope. This often means—as FDA reviewers have stated numerous times in the course of the last year—that multiple assays are likely required to fully characterize more complex products, such as CGTs. Likewise, even if an assay was designed to measure a particular property of interest, its usefulness should be considered as it applies to each scenario (e.g., the sensitivity of a test may be appropriate in one setting but may not be appropriate for another where the property must be detected and quantified at much lower levels).

Now the comments on the draft are in, and stakeholders had a lot to say

• The draft document was open for public comment for 90 days, during which time it received more than 160 comments. However, only 40 of these comments have been posted to the docket for public review. Additionally, six of these comments came from the same organization (Integrated DNA Technologies). It’s unclear why the majority of comments are unavailable for public viewing. As part of the eRulemaking Program, agencies may choose to redact or withhold certain submissions if they contain “private or proprietary information, inappropriate language, or duplicate/near duplicate examples of a mass-mail campaign.” In some cases, there is also a delay between comment submission, agency review, and the posting of comments online to the docket.
• In general, the FDA’s shift in approach on this topic seems to have generated more questions than answers. In particular, many comments cite the lack of context around certain changes made to the guidance and question whether the FDA’s incorporation of broader risk management principles is truly an attempt to streamline requirements or rather an attempt to impose new requirements beyond what is already commonplace (e.g., per the ICH Q6B and ICH Q9(R1) guidelines).
• One commenter – the U.S. Pharmacopeia (USP) – voiced support for the FDA’s new approach to the subject. The USP commended the FDA’s efforts with this guidance, stating that it “supports FDA’s revised approach for establishing CGT potency that will help to enhance patients’ access to these therapies.” It also noted that the alignment of this draft guidance with ICH Q9(R1) “will help to harmonize regulatory efforts – an essential step as more products undergo regulatory review.”
• Many of the remaining comments, however, showcased varied interpretations and sentiments on the draft document.

A number of comments posed overarching application-related questions to the FDA

• The Biotechnology Innovation Organization (BIO) wrote that although the updated guidance conceptually aligns well with other guidances (e.g., the ICH quality guidelines), the draft may “introduce redundancy, potentially causing confusion and inefficiency when implementing the outlined concepts in the development of a potency strategy.” The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium), another industry group, cited similar concerns, describing several of the recommendations in the new draft as “somewhat confusing,” “unclear,” and/or “unrealistic.
• Taking a different tack, the Alliance for Regenerative Medicine (ARM) affirmed the FDA’s “intent to encourage integration of potency assurance into overall product quality risk management and not to request duplicative efforts.” However, the organization asked that the FDA explicitly state in the final guidance that it does not “expect sponsors to develop an additional quality system specific to potency, but rather to ensure sponsors address potency as a component of the existing quality system, as many sponsors may already do.” ARM also stated that, “We appreciate the Agency providing this information to guide newer developers of CGTs, but we suggest clarifying that these are not new recommendations by identifying them as best practices that will assist CGT sponsors in meeting Agency expectations.”
• Some groups appeared receptive to the FDA’s strategy—at least in concept—but still voiced concerns regarding the breadth of the changes to the guidance. For example, BioPhorum (an industry group) stated that its members “welcome and appreciate that this guidance takes a holistic view of the potency control strategy.” However, the group also pointed out that some of the language used in the new draft appears to contradict what was conveyed in the 2011 guidance—an issue that could “cause a challenge for companies when transitioning to the new draft guidance.” To “ease the transition” from old to new recommendations, the group suggested that the FDA provide context for making these changes and provide examples of current expectations.
• On the opposite end of the spectrum, the American Society of Gene & Cell Therapy (ASGCT) expressed outright criticism on the application of these principles to early-stage products. While agreeing that there have been significant advancements in the manufacture of CGT products, ASGCT took issue with the FDA’s methods for addressing these developments. In short, the Society argued that establishing the potency of CGT products, particularly in early development, is difficult. Given these challenges, ASGCT asserted that “the information necessary to implement the multi-faceted strategy approach in the draft seems better suited for late-stage products, and this should be stated in the text.” The Pharmaceutical Research and Manufacturers of America (PhRMA) also voiced this concern, asking the FDA to provide “additional detail regarding phase appropriate implementation.”
• Echoing some of ASGCT’s concerns, many stakeholders requested further clarification on the application of potency assay(s) in early development. The IQ Consortium asserted that it is unlikely for sponsors to identify meaningful potency-related CQAs prior to the initiation of clinical studies. For this reason, the group instead recommended that the draft be revised to suggest that “initial potency-related CQAs be identified prior to studies being designed, which can provide primary evidence of efficacy,” or that sponsors may “describe preliminary/initial understanding of MOA, QTPPs, CQA in an IND as the basis for justifying human evaluation of a drug” with the expectation that their understanding of these areas would increase during the product’s lifecycle. Similarly, ARM suggested that the term “candidate potency-related quality attribute” be used in the early stages of clinical development to discuss product attributes that are thought to be linked to potency, but where the “criticality (mechanistic relationship) of the attributes” to product potency has not yet been established.

The majority of comments also called out specific concerns with the guidance

• A major recurring theme: The guidance’s broad recommendations should be supplemented with advice specific to different CGT product types. For example, there were several requests for the FDA to acknowledge and separate out some of its recommendations for cell therapies versus gene therapies, where different considerations apply. Some requested that the FDA consider potential differences in potency assurance strategies for allogeneic versus autologous cell-based products. Others, such as JDRF International (formerly, the Juvenile Diabetes Research Foundation), suggested that disease-specific guidance documents would be useful. Many stakeholders, like Halloran Consulting Group and PhRMA, urged the agency to issue more detailed guidances on potency assurance for different product modalities (e.g., for gene therapies that use viral or nonviral vectors).
• Stakeholders were divided on the elimination of the “assay matrix” terminology from the new draft document. Some—like ARM—applauded FDA’s move away from using this term, explaining that its use has created “significant developer confusion.” BioPhorum took a more agnostic approach, simply questioning whether this change was intentional and requesting that FDA make its stance clear in the final version. PhRMA, on the other hand, stated its understanding that the term was simply replaced, asking that the FDA “expressly state that the product quality attributes that were measured as part of a potency matrix approach (introduced in the 2011 Potency Guidance) and the ‘product’s initial CQAs’ are interchangeable (in practice).” Advanced therapy medicinal product (ATMP) experts organized under the ECA Foundation stated that the FDA’s endorsement of a potency assurance strategy over a potency matrix strategy, “is a significant change” which “neglects the benefits of a matrix approach, especially if the mechanism of action (MOA) of a new product is not fully understood in early phase of development.”
• Many commenters questioned why some of the information included in the 2011 guidance has been dropped from the new draft. BIO even included a “Gap Assessment” in an appendix to its comment letter, highlighting several points that the organization said warranted inclusion in the final version. BioPhorum concurred with these requests and strongly suggested that FDA reconsider adding back some of the language from the 2011 guidance, including Table 1, which previously laid out the common challenges associated with potency development which the group stated “could be updated with newer types of ATMPs not previously covered.”
• There was also some contention related to the FDA’s recommendation to develop several different potency assays in parallel, early-on; later discarding those that are less useful after further experience with the product is amassed. To this point, the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) requested further clarification as to how this process might look and which factors might be useful in selecting a “primary potency assay or determining relative ranges for multiple assays when the MOA is complex, there are challenges with establishing correlation to clinical outcome, or there is significant variability in patient responses.” Conversely, Boehringer Ingelheim disagreed with the suggestion for sponsors to develop multiple potency assays for early clinical studies, as this could eventually lead to a “general expectation for having several alternative qualified potency assays in place already for Phase I, leading to additional development packages in an already compressed timeline.” The International Society for Pharmaceutical Engineering (ISPE) took a more nuanced approach, requesting that the language be tweaked to indicate that multiple assays are often optional.Teeing off these concerns, a number of commenters also questioned the FDA’s mention of potential clinical holds in early-stage studies. The draft guidance provides two scenarios in which the FDA may choose to impose a clinical hold on a product: 1) if in any phase, there is failure to demonstrate potency assurance which could result in “unreasonable and significant risk of illness or injury” to subjects; and 2) if, in phases 2 or 3, an IND does not “provide adequate assurance of product potency.” Taking issue with the first scenario, BioPhorum asked: “As the intent of Phase 1 clinical studies is safety, not efficacy. What would be the basis for putting a phase 1 program on clinical hold due to potency issues?” The Society for Immunotherapy of Cancer (SITC) ventured that “such restrictions on early-stage studies may be inappropriate as potency measurements are still being refined” and countered that “It would be beneficial if the draft guidance clarified that for Phase 1 studies, potency may not be the hold reason for an IND.” Referencing the condition for phase 2 or 3 studies, PhRMA asked that the agency modify its language to clarify that such a hold would only apply in situations when the study is intended “to provide substantial evidence of effectiveness for a marketing application.”
• Should potency assurance plans be submitted? If so, how? Lonza, a contract development and manufacturing organization (CDMO) questioned whether the FDA is setting a new expectation for sponsors to file updated risk assessments at each stage of product development, and if so, at what interval would updates need to be submitted. Along the same lines, BIO stated that it would be helpful for the FDA to specify how potency strategy plans (PSPs) should be submitted in original INDs and provide a new guidance section with instructions for how this information should be filed and updated.
• Lastly, there were frequent requests for the FDA to add a glossary to the final version. Among them, the ISPE noted that distinct and important terms (e.g., strength, potency assay, and bioassay) appear to be used interchangeably in the guidance and that “It is crucial for the understanding of the nuances in the guidance to clearly distinguish the terms.” Similarly, the ECA Foundation suggested that moving definitions of important terms from the footnotes of the guidance into a glossary, and expanding the list of terms defined, would make the document easier to read and understand.

Is the approach taken in this guidance truly a surprise? Maybe not.

• Taken together, these comments reveal an interesting divergence in stakeholder reactions. Some organizations seem to be taking FDA’s shift in direction in stride, primarily offering feedback on specific details of the guidance rather than its overall approach. Others seem to be taken aback by this new approach, expressing concerns as to what these changes might mean for sponsors prepping to move their assets into early-stage clinical trials, and more broadly for all of industry moving forward.
• Those who are taking the guidance in stride may have participated in a series of six town hall meetings conducted between September 2022 and August 2023. Hosted by the Center for Biologics Evaluation and Research (CBER)’s Office of Therapeutic Products (OTP), these meetings were used as a venue for disseminating important information about chemistry, manufacturing, and control (CMC) considerations for CGT product development, maneuvering through critical junctures in CGT product development (e.g., moving from nonclinical to clinical studies or prepping for pivotal trials), and common manufacturing and quality control issues seen for gene therapies and rare diseases. These meetings provided a useful window into the current thinking of FDA reviewers and the issues they most frequently deal with during application review. They also ultimately provided a preview of the potency assay recommendations found in the new draft guidance. In contrast, stakeholders who have only been monitoring the FDA’s formal means of communication (i.e., guidance documents) on CGT products may have been taken by surprise.
• Additionally, sponsors who have dealt with these issues firsthand in the last several years may have seen some of these changes coming. Those whose trials have been halted by the issuance of a clinical hold are likely intimately familiar with the FDA’s expectations regarding product characterization, risk assessments, quality control measures, manufacturing process changes and more. In particular, potency has played a central role in some of the agency’s recent decisions to issue clinical holds or deny marketing approval. Sponsors on the receiving end of these decisions have included Pfizer, Editas Medicine, INmune Bio, Iovance Biotherapeutics, and Verve Therapeutics, just to name a few.
• Some of the major changes in this draft guidance were also foreshadowed by another recent draft guidance on manufacturing changes and comparability for CGT products. Some of the comments submitted on the potency assurance draft (e.g., regarding clinical holds) questioned concepts which were first introduced in this other draft guidance. While the scope of these guidances differs slightly, they overlap significantly from the perspective of practical application. For those who may have realized the implications of the previous guidance a little too late (i.e., after the comment period closed), the new draft may have provided a delayed opportunity to provide input on topics covered in both.
• Interestingly, not one comment mentioned that the other draft guidance on manufacturing changes instructs sponsors to consider the impact of an increase in product potency following a manufacturing change, “even if intentional.” That guidance explained that not only might an increase in product potency lead to safety concerns, but if the change is “such that there is a significant benefit in effectiveness and/or safety, then the post-change product may be considered a different product, and therefore not comparable to the pre-change product.” However, the potency assurance draft guidance does not mention the implications of increased potency, focusing instead on reducing the risk of administering “sub-potent” products to patients.

What’s next?

• It’s worth noting that the FDA received extensive stakeholder input during the OTP town halls, which likely already contributed directly to the content of this draft guidance. The town halls offered a way for stakeholders to ask questions without judgement and without the need to tie questions to a particular product or application under review. Thus, they also provided an opportunity for the FDA to gauge which aspects of CGT product development presented obstacles, where common points of confusion lie, and where guidance would be most useful in addressing these concerns. Given the timing of the town halls and the date this draft guidance was released, this interactive dialogue almost certainly overlapped the draft’s development.
• How might FDA respond to the feedback received in the comments? Many stakeholder concerns regarding the changes to the new guidance could be cleared up with further explanation from the agency about the reason behind these changes and how these new recommendations fit into existing requirements. Per the pre-recorded webinar that was posted alongside the draft guidance, it seems that the FDA’s intent was to streamline requirements for sponsors, not increase them. If this is the case, the FDA’s process to finalize the guidance should be relatively straightforward. That said, the manufacturing and comparability guidance was more extensive and explicit in its requirements; so, if taken together, the pair could indicate that the FDA really is ready to tighten the reigns when it comes to product quality assurance. Once either document is finalized, the agency’s intent should become clearer.
• Will the FDA supplement this newly broadened guidance with other guidance documents to address the unique considerations for certain subsets of CGT products? The new guidance differs from its predecessor in granularity, and its publication was not supplemented by any sort of explanation on what will happen with the specifics that were not carried forward from the prior version – a point with which many stakeholders took issue. Considering that the guidance stated, “FDA may issue additional guidance documents that provide further advice about potency assays for specific classes of CGT products,” it seems likely that the FDA intends to move some of that specific information to these future, supplemental documents. Although no such guidance documents appear on CBER’s 2024 guidance agenda, it is possible that the FDA could repackage some of this information into another guidance which is new to the CBER guidance agenda this year: Frequently Asked Questions: Cell and Gene Therapy Products.

To contact the author of this item, please email Rachel Coe ( [email protected]).
To contact the editor of this item, please email Chelsey McIntyre ( [email protected]).

Key documents

• Draft Guidance: Potency Assurance for Cellular and Gene Therapy Products
• Docket No. FDA-2023-D-4299: Potency Assurance for Cellular and Gene Therapy Products