Reducing The Number Of Clinical Holds On Cell And Gene Therapies: Approaches For Sponsors And The FDA

By Sandy Kweder and Sean Hilscher, Eliquent Life Sciences

With the FDA initiating a number of programs to support the clinical development and regulatory review of cell and gene therapies over the past year, it is opportune to address a lingering concern: the large proportion of trials for cell and gene therapies placed on clinical hold. The FDA has attributed this to an overall increase in clinical holds issued by CBER due to the growing volume of clinical trials planned or initiated for cell and gene therapies.¹ Nonetheless, a recent analysis noted that cell and gene therapy trials accounted for 40% of the total number of FDA clinical holds in spite of representing only 2% of trials listed on ClinicalTrials.gov.² While this imbalance may partly reflect the newness of the science in this field, and the fact that many cell and gene therapy products are first in class, the rate of holds seems disproportionate. If nothing else, it warrants an assessment of what underlies the trend beyond the nature of the products themselves, with an eye toward preventing future holds.

Especially when prolonged, clinical holds may delay patient access to potentially beneficial investigational products and certainly have financial implications for companies. Even more concerning is that in the latter circumstance, a real risk is programs being abandoned due to lack of funds, further depriving patients and physicians of promising treatment options. In cell and gene therapy development — where medical need is great, technology rapidly evolving, and the business model so precarious — sponsors and the FDA have a shared interest in making clinical holds a rarity.

As regulatory consultants working across the spectrum of product developers, from small to large firms, we often work with developers seeking assistance with resolving the issues that results in the hold. Here we offer advice to sponsors on proactive strategies to increase the likelihood that their program will progress without a clinical hold. We also propose complementary approaches that the FDA could adopt to ensure that clinical holds are placed on cell and gene therapy programs only in necessary and unavoidable situations.

Clinical Holds On Cell And Gene Therapies: Perception Versus Reality

How common are clinical holds on cell and gene therapy trials, in fact? It is difficult to determine the precise number, but based on publicly disclosed information, we estimate that at least 136 cell and gene therapy trials have been placed on clinical hold since January 2020. Given the perception that the number is inordinately high, the annual number of holds has nonetheless declined from a peak of 147 in 2018 to a low in recent years of 70 in 2022, according to an analysis by The Pink Sheet conducted with data obtained through a FOIA request.³

When seeking to understand the current universe of clinical holds, it is essential to examine the specific reasons they are applied in the first place. The majority of clinical holds have been implemented in response to adverse events or patient deaths, many of which are not predictable. Meanwhile, the second most common cause of clinical holds on cell and gene therapy programs appears to be missing or problematic chemistry, manufacturing, and controls (CMC) data, including observations during inspections of manufacturing facilities. Manufacturing gene and cell therapies presents unique challenges that FDA is particularly attentive to. Sponsors in the cell and gene therapy fields are often academic researchers or smaller companies with little prior experience navigating FDA regulations and procedures, which makes scale-up to commercial manufacturing facilities and processes particularly challenging. This often results in difficulties establishing comparability between the investigational product and the proposed commercial product and ultimately leads to inconsistencies in CMC data packages.

What happens to development programs after a trial is placed on hold? One study found that approximately 80% of clinical holds identified in the two-year period between 2020 and 2022 (n=33) were formally lifted after an average duration of 6.2 months, though some lasted over 19 months (time frames include two thirty-day periods allotted for CBER to issue formal comments and subsequently review a complete response from the sponsor).⁴ Outcomes are highly variable. Several trials faced a clinical hold, yet once the cause had been addressed, those trials resumed and achieved significant positive results. By contrast, one trial was discontinued because of safety issues before the hold was lifted, and three more proceeded following removal of the hold but were discontinued very soon after.⁵

Bluebird Bio’s experience provides some insight into these data. The company has achieved three approvals for its lentiviral gene therapy products, each following a clinical hold. For two of these products that use the same lentivirus vector, Zynteglo (betibeglogene autotemcel, indicated for beta-thalassemia) and Skysona (elivaldogene autotemcel, indicated for cerebral adrenoleukodystrophy), the clinical holds were placed in 2021 after several trial participants developed myelodysplastic syndrome (MDS). The holds were lifted and the products granted approval in 2022, after the Cellular, Tissue, and Gene Therapies Advisory Committee voted to recommend approval on the basis that the benefits outweighed the risks of malignancy.⁶ Bluebird’s most recently approved lentiviral gene therapy, Lyfgenia (lovotibeglogene autotemcel, indicated for sickle cell disease), was subject to two clinical holds — the first occurred in 2021 and also was prompted by a diagnosis of MDS in a trial participant. The second hold was a partial hold that applied to patients under age 18, as a result of persistent, non-transfusion-dependent anemia in a patient in that age group. The cause was ultimately determined to be an underlying genetic condition, allowing the hold to be lifted with procedures in place for subsequent trials to screen patients for this condition.⁷

While the experience of Bluebird in overcoming clinical holds is encouraging, the objective for sponsors should be to continue to avoid a clinical hold altogether. The recommendations in the following section will further that aim and, moreover, support the overall success of the clinical program.

Sponsors: Know Your Regulators

At the outset, sponsors can anticipate adverse events and other concerns that are associated with their product class and technology, though there will always be surprises due to the nature of the human response to these products. As the field develops, the risk profiles of certain product classes will likely become more predictable but, for now, much is still being learned by investigators, companies, and regulators. Unfortunately, regulators often cannot make such learnings public due to commercial confidential nature of data. However, we suggest there are ways for sponsors and investigators to gain insight into FDA thinking.

• Labels and reviews. The language in labels provides good insight into the clinical trial decisions that a new sponsor may be facing. Similarly, the integrated reviews, published after an approval decision, is an invaluable resource for sponsors on the nonclinical and clinical trial designs that are acceptable to FDA.

• FDA Advisory Committees provide a wealth of information and insight. In September 2021, FDA convened a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee to discuss and make recommendations on various toxicity risks associated with adeno-associated virus (AAV) vector-based gene therapy products.⁸ Advisory committee meetings on individual product BLAs also furnish information about risks and how the agency and the professional community regard those risks in relation to the evidence of potential benefit.

• Learn as much as possible about reasons for other products being placed on hold. Sponsors should seek all information about their technology and product class in general, as well as the risks specific to their own product. FDA presentations at conferences often provide a great deal of information as the staff provide summary overviews (often with an unidentified product) of their concerns. With respect to gene editing technologies, for instance, the FDA has expressed concerns about the potential for off-target editing, with at least one gene-edited therapy placed on clinical hold in part because the agency wanted to see additional analyses in this area.⁹

• Guidances matter, even when they are in draft form. The FDA has provided draft guidances on the development of gene therapy products that utilize human genome editing, as well as guidance on CAR T cell products and gene therapy products for several disease categories.¹⁰ The agency takes great care when writing guidance documents to focus on experience already at hand, even though individual products are not named.

• Preclinical data is even more important in cell and gene-based therapies, so use it well. Known risks and concerns should be comprehensively assessed in preclinical studies and factored into the risk assessment plan submitted in the IND application, along with a plan for how to address safety issues if they arise in clinical trials.

• CMC is a first order of business. Although most clinical holds are prompted by safety events, a number have resulted from CMC deficiencies (at least nine therapies in the past three years), preclinical data, or other elements of the program. CMC deficiencies can be especially costly in terms of the time required to remedy the issue. The 2023 study cited above found that CMC issues took an average of 8.4 months to resolve, significantly longer than the four to six months on average that it took to assess adverse events or address FDA requests for protocol amendments or preclinical information.¹¹ In many cases, a better understanding of the FDA’s expectations and requirements through existing guidances could have enabled the sponsor to address the reason for the hold prior to submission, a circumstance we have seen many times with clients.

A good example is potency assays. To avoid CMC issues and holds, potency assays must be developed and refined during the preclinical and early clinical stages of development. A recent draft guidance, Potency Assurance for Cellular and Gene Therapy Products,¹² provides strategies for assuring the potency, or specific ability of a product to have the intended therapeutic effect across every lot of product released. The draft guidance also specifies the FDA’s recommendations for potency assay selection and design, control and change management, and acceptance criteria within a comprehensive risk-based approach to potency. The draft guidance notes that if the potency of an investigational product cannot be assured, or if the IND does not contain adequate information to assure potency, then the study may be placed on clinical hold. Further, the guidance explains that if the IND for a Phase 2 or 3 trial does not provide assurance of product potency, the design of the trial is compromised in its objective to provide evidence of effectiveness to support licensing, which is also grounds for the FDA to place a clinical hold.¹³

• Engage FDA and others. In the area of gene therapy manufacturing and controls, CBER’s director recently noted the need for companies to engage not only directly with the FDA but across the industry and academia, in order to identify best practices that could potentially be solidified into standardized manufacturing processes and platforms.¹⁴ To prevent potential CMC and preclinical complications, sponsors should engage with the FDA by requesting meetings at the early predevelopment stage through the Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) program and at the pre-IND stage through pre-IND meetings. While the meeting request process can seem prolonged, ultimately, they are almost always a good investment. Such meetings afford sponsors opportunities to ask specific questions of FDA staff regarding their program and to seek clarification on FDA guidance.¹⁵

• Seek help. Small academic centers and emerging companies understandably may lack resources to know all of the FDA guidances, which are numerous and quite detailed, much less how the guidances interface with each other or what to expect in the process of interaction with the agency. In addition to meeting directly with the FDA, working with experienced regulatory consultants who know and thoroughly understand FDA guidances and expectations can often be the most efficient route to success. A clinical hold will bring costly delays to a program, in terms of both time and financial resources, so obtaining strategic guidance at the outset can be a wise investment.

Consultants also can advise sponsors on which designations (e.g., RMAT, breakthrough therapy) their product might be eligible for and guide them through the process of requesting a special designation. If a product meets the requirements — which include preliminary clinical evidence — the sponsor will gain the advantage of earlier and closer interactions with CBER review staff. The FDA dedicates extra resources and attention to products with these designations in light of the early evidence of potential effectiveness. Note, however, that 90% of applications received by the Office of Tissues and Advanced Therapies (OTAT) were for serious or life-threatening diseases, and half were for rare diseases, and therefore the office’s resource constraints still apply. Further, a designation is not a guarantee that all problems potentially leading to a clinical hold will be identified in advance; programs with RMAT and breakthrough therapy designation have been put on hold.

• It is not personal. Sponsors must be receptive to the feedback offered by the FDA during pre-IND and INTERACT meetings and incorporate agency advice into their INDs. Don’t forget that FDA may be advising you based on another sponsor’s experience, but the details cannot be shared.

• Focus on the details. Finally, at the most fundamental level, IND and meeting packages must be complete and detailed. For example, more than one CAR T cell therapy trial was placed on clinical hold because the IND lacked sufficient information to support a risk assessment of subject safety.¹⁶

FDA: Consider The Risks

CBER Director Peter Marks has acknowledged that the increase in clinical holds has been driven, to some degree, by the center’s difficulty in processing the sheer volume of IND applications for cell and gene therapies with the current number of reviewers on staff. We emphasize the significance of this issue and the need to augment the center’s review capabilities — not simply because a more robust staff would be better able to meet the demands of processing applications within the initial 30-day IND cycle, but also because review staff would have greater capacity to interact with sponsors during that 30-day period and attempt to resolve any issues that otherwise might, without such time and attention, lead a reviewer to default to a clinical hold. Further, CBER’s ability to conduct INTERACT and pre-IND meetings, as we have recommended above, is also contingent on the number of staff available.

We applaud FDA’s recent measures to augment its review staff dedicated to cell and gene therapies and efforts to instill greater flexibility into its processes, efforts primarily facilitated by the recent reorganization of the previous OTAT into the Office of Therapeutic Products (OTP). With the formation of OTP, the FDA intended to hire 132 new review staff specifically dedicated to cell and gene therapy product reviews; however, recruitment for these positions has been a challenge due to the salary discrepancy between the government and the biotechnology industry. The same reality has affected retention of senior review staff, draining significant expertise in recent years as the number of applications for cell and gene therapy products has escalated.

Lastly, to ensure innovation and development continue at the same pace, we encourage FDA to continue to share information on safety concerns observed with particular therapeutic classes, without compromising confidentiality of IND holders, so that sponsors can proactively prepare (e.g., through public and sponsor meetings, advisory committees, comments at conferences or in publications, as well as in guidances) and avoid clinical holds.

References

1. Liz Essley Whyte, “FDA Increasingly Halting Human Trials as Companies Pursue Risky, Cutting-Edge Drugs,” The Wall Street Journal, January 10, 2023.
2. Wills CA, Drago D, and Pietrusko RG. "Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned." Molecular Therapy: Methods & Clinical Development. Vol. 31. December 2023. https://doi.org/10.1016/j.omtm.2023.101125.
3. Brenda Sandburg, “Gene And Cell Therapy Clinical Holds Decline While Those For Drugs Hit 12-Year High,” The Pink Sheet, September 25, 2023, available at https://pink.citeline.com/PS148691/Gene-And-Cell-Therapy-Clinical-Holds-Decline-While-Those-For-Drugs-Hit-12-Year-High.
4. Wills 2023. [see Ref. 2]
5. Ibid.
6. Ibid.
7. Ibid.
8. Cellular, Tissue, and Gene Therapies Advisory Committee September 2-3, 2021 Meeting Announcement. U.S. Food and Drug Administration Website. Updated 11/24/2021. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-september-2-3-2021-meeting-announcement.
9. Beam Therapeutics, Inc. Form 8-K. August 25, 2022.
10. See complete list of FDA guidances for Cellular and Gene Therapies on the FDA website: https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances
11. Wills 2023. [see Ref. 2]
12. U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. “Potency Assurance for Cellular and Gene Therapy Products: Draft Guidance for Industry.” December 2023. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/potency-assurance-cellular-and-gene-therapy-products.
13. Ibid, p. 4.
14. Brenda Sandburg, "Gene Therapy Manufacturing: US FDA Wants Academics Brought ‘Into The Loop,'" The Pink Sheet. January 18, 2024.
15. CBER has also announced a new program, Support for Clinical Trials Advancing Rare Disease Therapeutics (START), modeled after Operation Warp Speed, which expedited vaccines development during the COVID-19 pandemic. Similarly, the intent of START is to facilitate the clinical development of therapies for rare diseases by providing sponsors with direct, real-time advice from CBER.
16. Wills 2023. [see Ref. 2]

About The Authors

Sandra Kweder, M.D., is an internal medicine expert with more than 30 years of experience in U.S. and international medical products regulation and policy. As principal, drug and biological products, with Eliquent Life Sciences (Greenleaf Health), she offers broad expertise accrued through senior leadership roles at the FDA, where she oversaw significant regulatory developments during periods of transformation in the landscape of science policy and public health. Kweder recently served for six years as deputy director of the FDA’s Europe office and liaison to the European Medicines Agency (EMA). Prior to her work in Europe, she spent nearly 14 years as deputy director of the Office of New Drugs (OND) in the FDA’s Center for Drug Evaluation and Research (CDER). She trained in medicine at the Uniformed Services University in Bethesda, MD, and performed her two-year clinical teaching fellowship in obstetrics and consultative medicine at Brown University School of Medicine.

Sean Hilscher is vice president of regulatory policy at Eliquent Life Sciences (Greenleaf Health). He works with clients on a range of regulatory and policy issues, including real-world evidence and digital health. Prior to Greenleaf, he managed a suite of real-world evidence platforms for providers, payers, and life science companies. He has an MBA from Georgetown University and an MA in politics, philosophy, and economics from the University of Oxford.

Greenleaf Health has joined forces with Eliquent Life Sciences.