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Drugmakers Face Uncertain Regulatory Pathways in Bringing Novel Cell Therapies to Market

Infusion bag

NEW YORK – Drugmakers developing autologous cancer cell therapies are struggling to navigate uncertain regulatory requirements and are asking agencies to provide concrete guidance on approval criteria.

Autologous cell therapies are n-of-1 treatments that involve harvesting a patient's immune cells, genetically modifying them so they recognize cancer targets, then treating patients with those cells, usually as a single infusion. The patient-specific nature of the treatment presents unique challenges for drugmakers who are used to standardized manufacturing processes for scaling up pharmaceutical products for a population of patients.

While a handful of major players in the space, including Novartis, Gilead/Kite, and Bristol Myers Squibb, have garnered approval for CAR T-cell therapies for advanced blood cancers, other drugmakers including academic lab spinouts and small biotechs have faced hurdles in trying to show regulators that their products are safe for patients, effective at treating their cancers, feasible to produce on a commercial scale, and reliably potent in their anti-cancer activity.

Regulators similarly find themselves on new ground in having to guide drugmakers on how to prove these factors. The US Food and Drug Administration has been slow to adopt hard-and-fast standards for cell therapy regulation. Instead, the agency has taken a case-by-case approach to reviewing products' potency assays, deciding whether one firm's product differs enough from another's, and ensuring a product's manufacturing capacity can meet commercial demand.

The FDA is accustomed to regulating off-the-shelf drugs for which each individual pill or infusion is identical, and doesn't have a framework it can neatly apply to regulating products that fundamentally differ from patient to patient. As a result, when it comes to cell and gene therapies manufactured from patients' own cells, the regulatory process can often seem as bespoke and variable as the products themselves.

'All things are on the table'

In the five years since the first autologous CAR T-cell therapy, tisagenlecleucel (Novartis' Kymriah/tisa-cel), entered the commercial market for relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), the number of drugmakers developing cell therapies has skyrocketed. As of June, there were over 1,358 active cancer cell therapy trials — including 668 CAR T-cell therapy trials — globally, representing a 78 percent increase compared with 2019. But just five cell therapies, all autologous CAR T-cell products targeting CD19 or BCMA, are currently FDA-approved for various advanced blood cancers. For some patients, these therapies have been lifesaving.

The success of these first CAR T-cell therapies has jumpstarted the cell therapy space with drugmakers advancing autologous tumor-infiltrating lymphocytes (TILs), macrophages, NK cells, and T-cell receptors, among other approaches. But as more industry players have entered the space, it has placed stress on a regulatory apparatus unprepared to handle the volume and complexity of these products.

"The clinical review of these [cell therapy] products frequently poses more challenging questions than reviews of more conventional drugs," an FDA spokesperson wrote in response to questions via email. Potency assays, in particular, are among the biggest regulatory hurdles for companies developing these bespoke products.

The FDA requires that all drugmakers seeking approval for biologics lay out their plans for ensuring consistent product activity — dubbed potency — along with sterility, purity, and identity. The agency defines potency as "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." According to those involved in developing cell therapies, however, the FDA stops short of prescribing what, exactly, a drugmaker must present as a potency assay.

Biotech firm Iovance has experienced several setbacks trying to commercialize its autologous TIL product lifileucel for metastatic melanoma due to potency assay issues. In 2019, Iovance first announced plans to file a biologics license application (BLA) with the FDA for lifileucel based on durable benefit in melanoma. The firm remains confident that it will bring the therapy to market and has even constructed a manufacturing facility in anticipation of scaling up production to meet commercial demands. But two years later, despite several confirmatory results readouts on the product, Iovance's lifileucel BLA is still pending.

The delay, according to the firm, has to do with the FDA's concerns about how Iovance will ensure each patient-specific iteration of lifileucel has reliable activity before infusion.

"The types of things [the FDA] is looking for [with a potency assay] are things like cytotoxic actions … Whether the effector molecule is doing what you expect it to do," explained Bambi Grilley, director of clinical research and early product development at the Baylor College of Medicine's Center of Cell and Gene Therapy and a member of the International Society for Cell & Gene Therapy (ISCT)'s North America Legal and Regulatory Affairs Committee.

For two of the first CAR T-cell therapies the FDA approved, Gilead/Kite's axicabtagene cileleucel (Yescarta/axi-cel) and tisa-cel, the agency accepted potency assays that involve co-culturing each product with a cell line expressing the target antigen, then measuring interferon gamma release using ELISA assays as a signal of immune activity. A potency assay must be performed for each manufactured product before it is infused in the patient. While such in vitro assays don't guarantee the therapy will benefit the patient — interferon release is technically a surrogate measure of activity — they sufficiently convinced the FDA that there is a level of immune response activity with axi-cel and tisa-cel.

But because of the diversity of T-cell phenotypes and functions in each cell therapy product and patient, potency is "one of the least understood end product critical quality attributes of the CAR T-cell therapy drug product," Sadik Kassim, Kite's former executive director and current chief technology officer at Vor Biopharma, wrote in a 2017 Cell & Gene Therapy Insights paper.

"Neither [interferon gamma] nor the cytotoxicity assay are predictive of overall clinical efficacy and safety," Kassim wrote, acknowledging that the data the FDA accepted as demonstrating potency of Kite's axi-cel relies on a surrogate measurement.

Meanwhile, for Iovance's lifileucel, the regulatory delays suggest the firm has yet to present the FDA with an acceptable potency assay and accompanying validation data. The firm hasn't disclosed the details of the specific assay it planned to use when it initially announced the BLA, but in a call with investors in June, Iovance executives said the firm is now considering using alternative assays either in combination or in place of the original assays. "All things are on the table with the FDA," said Iovance President and interim CEO Fred Vogt.

The comment gets at the heart of the challenges facing cell therapy regulation. The field is new, and regulatory agencies haven't provided many hard and fast standards. FDA's own guidance document about potency assays states that the agency allows for "considerable flexibility in determining the appropriate measurement(s) of potency for each product."

This has been a challenge for risk-averse drugmakers who prefer more specific regulatory criteria. "What we really want from the FDA is some level of consistency," said Timothy MacLachlan, Novartis' executive director of preclinical safety and a member of the American Society of Cell and Gene Therapy (ACGT)'s regulatory affairs committee. "It's an age-old problem."

According to MacLachlan, some firms have tried to use tests that measure the CAR or T-cell receptor expression on the manufactured cell, which he called a "really weak potency assay," because it isn't showing activity so much as confirming that the manufacturing process succeeded in making a harvested cell express the intended receptor.

"Searching for alternative potency assays that are more predictive of activity … is a lot easier said than done," he acknowledged, explaining how measuring cell therapy potency requires "orders of magnitude more complexity" than proving potency for, say, traditional small molecule drugs.

As Grilley recounted, in a talk given to members of ISCT last year, Peter Marks, director of the FDA's Center for Biologics Evaluation and Research (CBER), suggested that firms "pick something — anything — to show [they] can consistently manufacture the product."

"Pick anything" struck Grilley as a very different message from the more prescriptive language that drugmakers are accustomed to hearing from the FDA. In addition to flexibility, the agency has also encouraged drugmakers to try using combinations of assays to collectively demonstrate the product's consistency rather than single assays, which may not cut it.

"Potency assays are one of the most difficult things to standardize within this arena," Grilley said, adding that in traditional drug development potency is measured using more standard processes, "When you get to autologous products, it could be all over the place."

With non-biologic drugs consisting of small molecules or straightforward chemicals, molecular weight might be sufficient to demonstrate potency. And even with biologics, like monoclonal antibodies that do require more functional measures of potency such as cell-based assays designed to capture cytotoxic activity, the manufacturer would theoretically only need to perform that test once for each lot of the product, since every product within the lot would be the same. With an autologous cell therapy, though, each patient's treatment is its own "lot." The assay, therefore, needs to be one that manufacturers can use on every individual treatment.

These challenges make it crucial for drugmakers to start communicating with regulators about potency assessment plans from the earliest development stages. This challenge isn't unique to the FDA, either, according to Massimo Dominici, past president of ISCT and scientific founder of Italian biotech  Rigenerand, which is developing mesenchymal cell-based gene therapies for pancreatic cancer.

In Dominici's view, drugmakers should begin developing potency assays with the start of human trials in Phase I based on regulatory discussions they had in preclinical stages. "If you wait until Phase III, you may not have time [to validate it]," he said. "Potency assays should be developed in parallel with the clinical applications."

Despite the absence of standard regulatory criteria for these assays, both MacLachlan and Grilley noted that the FDA has been communicative with drugmakers and open to suggestions. "[Conventional] drug development tends to be much more rigid, with the FDA saying, 'These are the parameters we need you to hit,'" Grilley said. "With CBER, they've been much more collaborative, saying, 'You tell us what you think will work and we'll tell you whether we consider it acceptable.' There's much more of a dialogue."

In early 2020, the agency issued a series of guidances for industry in an attempt to address manufacturing and other aspects of cell therapy development. Despite these efforts, there is still substantial uncertainty among industry players in this space.

The agency itself seems more willing to accept ambiguity in regulating cell therapies. "The clinical review of these products frequently poses more challenging questions to regulators than reviews of more conventional drugs … and these questions often can't be fully answered in pre-market trials of reasonable size and duration," the agency wrote in a statement accompanying the guidance documents. For some products, the FDA acknowledged it "may need to accept some level of uncertainty."

'Sameness' uncertainties

Beyond the potency assay challenges facing these bespoke products, questions remain regarding what factors the FDA considers sufficient to differentiate cell therapy products from one another for the sake of obtaining orphan drug status — a designation intended to incentivize development of rare disease drugs by awarding sponsors tax breaks and seven years of market exclusivity. In traditional drug development, if a sponsor is seeking orphan status for a therapy in an indication where other marketed drugs are considered the "same" from a regulatory standpoint because they have the same active ingredient or molecular structure, then the sponsor must show its product has greater efficacy or safety or makes "a major contribution to patient care" compared to those other products.

As the cell therapy space becomes more crowded, drugmakers increasingly want to obtain the financial incentives that come with orphan designation, but according to MacLachlan, companies are having trouble demonstrating how their therapies differ from other products. In a guidance document, entitled "Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations," the FDA said that two cell therapies that go after the same target using the same biological mechanism could be "different products" if two different viral vectors — which are used to transduce genetic information into a cell and direct it at specific targets — are used to engineer the product.

The agency complicated matters, however, by adding that products using two variants of a vector from the same viral group could be the same or different, depending on the circumstance, and that it will make these determinations on a case-by-case basis. Industry players and professional societies have pushed back on this part of the guidance and asked the agency for more clarity.

"FDA should identify the criteria it will use to decide whether two viruses from the same class are the same or different to provide greater certainty," wrote representatives from the Pharmaceutical Research and Manufacturers of America (PhRMA) trade organization in a comment. "FDA should also explain what standard it will use for vectors not derived from viruses but instead from plasmids or bacteria."

However, in finalizing this guidance last month, the agency added minimal context and continues to state that it will make case-by-case decisions on the sameness of variant vectors from the same viral group.

Novartis' MacLachlan understands why the agency may be reluctant to issue more specific criteria for these types of decisions. "I sympathize with my health authority colleagues because there's so much that they're learning as each sponsor brings in a data set … about how these products are behaving in a manufacturing sense, a safety sense, and a clinical and efficacy sense," he said. "They're really resistant to put hard and fast rules in place because there's still so much variability in the products."

The agency likely doesn't want to draw any lines in the sand about what they'll accept, MacLachlan continued, because "they'll find themselves immediately having to break that rule with the next sponsor that comes to the door."  

Industry stakeholders, still wanting more guidance, have suggested regulators and companies collaboratively compile case studies where the FDA determined products were the same versus different, but MacLachlan said this has yet to materialize.

Scaling up

Beyond potency assays and differentiated products, regulatory agencies want to ensure that cell therapy products can realistically meet commercial demands. This presents an added challenge given that cell therapies usually originate in small, academic labs with manual manufacturing processes.

From a manufacturing and administration standpoint, autologous cell therapies are far more variable from patient to patient than traditional drugs manufactured using automated processes on an industrial scale. Each cell therapy product is harvested, engineered, expanded, and reinfused under the supervision of a dedicated team that can tweak infusion timelines and make manufacturing adjustments so it has the highest likelihood of success for a patient. Patients must be admitted to specialized hospitals to receive treatments under the supervision of care teams who can mitigate adverse events like cytokine release syndrome, or adjust dosage as needed.

The whole course of therapy is less like a drug than a medical procedure, according to MacLachlan. "The only time the agency has ever come close to something like this is with bone marrow transplants," he said. "This is very much a new thing."  The FDA does require that "minimally manipulated" bone marrow transplants meet certain criteria, but it does not subject them to the same intensive regulatory processes that biologic products must navigate.

As Vered Caplan, CEO of Orgeneis, a firm developing automated point-of-care models for cell therapies, explained previously, because the manufacturing process is a significant part of the cell therapy product, companies that validate their therapies with manual approaches and then attempt to scale up and automate later can wind up having to revalidate everything.

"The cells you're manipulating are extremely sensitive," Caplan said. "If you change your manufacturing to an automated or industrial fashion, you're actually getting another product." This means that if a firm submits to the FDA validation data on its cell therapy product using manual processes, it cannot then pivot to an automated approach to scale up manufacturing for the market once the therapy is approved.

"In this field, an awful lot of the discovery is happening in academia," Grilley said, estimating that academic facilities following Good Manufacturing Practice standards are making maybe 30 cell therapy products for patients in a Phase I trial. But if the treatment progresses to later development stages, the university usually sells it to a pharma or spins out a commercial entity to take the product further. At this point "the product is leaving the itty bitty GMP [facility] and going out into the real world," she said, and again, the new sponsor must revalidate the manufacturing processes.

According to Grilley, these manufacturing challenges force sponsors to face potency assay uncertainties again. When a developer tweaks its manufacturing to reach more patients or improve turnaround times, it must use an acceptable assay to show the FDA that the product has consistent potency.

Overextended, under-resourced

The FDA has been in the business of protecting consumers from unsafe drugs since 1906, but its authority to regulate biologics began in 1972, when the responsibility was transferred from the National Institutes of Health's Division of Biologics Standards. CBER, the division now responsible for regulating autologous cell therapies, originated in the late 80s, predating commercialized autologous cell therapies.

Over the years, the agency has adjusted its regulatory frameworks to keep up with scientific advances. When immunotherapies in the form of monoclonal antibodies came along, like Genentech's trastuzumab (Herceptin), those also didn't fit neatly into existing regulatory frameworks. But with each new therapeutic modality, FDA personnel within CBER and its counterpart, the Center for Drugs Evaluation and Research (CDER), have restructured and reconfigured regulatory processes to ensure the agency can evaluate product safety and efficacy.

The agency must now evolve its processes again for autologous cell therapies, and as Grilley noted, she has "found the CBER team to be very, very interactive and agile." But having multiple meetings with each cell and gene therapy sponsor eager for CBER's feedback before they start human drug trials may overextend the agency's expertise and resources.

"It's recognized by everybody that FDA is under-resourced in this area," Grilley said. "When you look at CBER and CDER … There's just not enough people in the ranks coming up." According to Grilley, the shortage of cell therapy expertise doesn't just impact the FDA but also the field at large. "You don't go to school to learn this," she said.

The FDA and ISCT are trying to cultivate a more robust workforce by setting up training programs and fellowships in cell therapy. Industry observers doubt these programs will fortify the regulatory ranks enough for FDA to keep pace with drugmakers developing these therapies. "The reality of a [case-by-case approach] is that … because these things are so ill-defined, you're going to have to have a discussion with the FDA," MacLachlan said, and the list of companies wanting to see the agency about cell therapy products is long.

The FDA offers sponsors multiple opportunities to discuss issues though the drug development process through a variety of different kinds of meetings, but lately, Novartis has had trouble getting on the agency's roster. "We've had meetings not approved for us recently because they don't have the resources [to accommodate] these burgeoning pipelines of ever more complicated products and processes that need guidance," MacLachlan said. "They don't have the people or time to address it for everybody."

Going global

Drug development tends to be global and the FDA is only one country's regulator. Firms interested in conducting cell therapy trials in multiple countries have to deal with different agencies with unique requirements.  

Globally, the space has a long way to go to reach standardization in development and manufacturing, let alone agreement on what defines a cell therapy. Recently, the regulatory bodies and pharmaceutical industry members of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) issued a draft guideline that categorized "ex vivo genetically modified human cells" as gene therapies. Under this and FDA's definition, genetically modified autologous cell therapies are technically gene therapies. The ICH document is expected to be finalized in 2022.

"Each country has its own flavor" when it comes to manufacturing and product release controls, Rigenerand's Dominici observed. But these seemingly "little differences might become big differences at the end when you're transferring your product into the clinic."

Grilley added that regulatory bodies in different countries have different aspects of the drug development process they are lenient and strict about. However, the formation of international consortia like ISCT shows there is a "real push for consistency and collaboration," she said, noting that ISCT is planning a meeting of regulatory leaders next year to discuss standardization issues.

Despite the challenges and uncertainties, drugmakers and regulators are motivated to move the cell therapy field forward because they know cancer patients who are out of options are waiting for these new treatments. "We're all just trying to figure it out as we go along," Grilley said.