Evolving Tools and Perspectives for the Development of Cell and Gene Therapies


Stakeholders must alter their mindsets when it comes to early-phase design and interpreting regulatory guidance for CGT trials.

Amy Raymond, PhD, PMP

Amy Raymond, PhD, PMP

This year marks the first time multiple gene therapies for the same non-oncology rare disease may be market authorized in the United States. They include treatments for beta-thalassemia, hemophilia B, and potential treatments for sickle cell disease.1,2,3

With the FDA predicting the approval of 10 to 20 cell and gene therapies (CGT) every year starting in 2025, the industry is at a significant turning point.4 Some of these therapies can potentially create durable change in the lives of vulnerable patient populations. Therefore, clinical trials to develop these advanced therapeutics carry a different risk tolerance—and a different value assessment—than many other product types. For example, clinical holds in cell and gene therapy programs can rightly be viewed as valuable “risk mitigation” measures, rather than harbingers of failure.

There are many ways in which cell and gene therapies require industry stakeholders to alter their traditional mindsets regarding risk, such as their opinions about the possible value of innovative trial designs and clinical holds. Thus, this article will explore the following:

  • Why clinical holds in CGT trials must be viewed differently than in other types of development programs.
  • How innovative designs benefit early-phase CGT development by uncovering the most promising versions of a treatment.
  • Key takeaways from FDA’s recent guidance on early-phase CGT umbrella trials exploring multiple versions of a product.

Clinical holds: Responsible risk moderation

The number of FDA-imposed clinical holds is rising swiftly, driven partly by an increasing number of innovative technologies and treatment modalities.5 While clinical trials to develop a CGT represent a relatively small minority of the development space, about 40% of clinical holds are for these programs.6

Traditionally, of course, clinical holds are considered undesirable. Not only do these holds delay programs, but they also often negatively influence investors, sites, and patient perception and participation. Yet, despite the logistical and financial complications they may cause, clinical holds on CGT trials should be viewed as responsible, risk-moderating measures that help ensure the ultimate development of safe and efficacious new treatments. These holds are not necessarily an obvious sign that a program is less than promising. Rather, they indicate that we are all paying close attention to each participant from the relatively small and often vulnerable patient populations involved in these trials.

This perspective may not be intuitive for all observers. However, given that some CGTs offer what are intended to be durable treatments for diseases with few other options, an abundance of caution is appropriate. In any study, the risk formula could be described as Risk = Impact x Probability. In the case of CGTs, the “impact” portion of the equation is often high and durable. So, even if the “probability” is low, responsible parties rightly hit the brakes at the first sign of a potential problem.

One industry editorial notes, “A clinical hold can be nothing more than a right-angle check—a ‘time-out’ taken to check your work. It can even be self-instigated by the sponsor company.”7

Indeed, out of the above-mentioned abundance of caution, some sponsors voluntarily pause a trial when an unexpected outcome is detected. For instance, sponsors voluntarily delayed a study examining a gene therapy for hemophilia A after a participant developed deep vein thrombosis. FDA subsequently added, then lifted, its own clinical hold.8 Another sponsor voluntarily paused its Phase I/II trial of a gene editing therapy for sickle cell disease after the first patient dosed experienced a serious adverse event.9

Being put on clinical hold by FDA is not necessarily a prognosticator for whether a product will be found unsafe. Research indicates that the majority of FDA-imposed clinical holds are eventually lifted.6 A recent meta-analysis of 255 trials involving the development of adeno-associated virus (AAV)-vectored gene therapies saw 30 clinical holds, 18 of which were related to toxicity findings.10 In fact, each of the past two years saw the approval of a gene therapy that had previously experienced an FDA-imposed clinical hold, including Skysona and Hemgenix.11,12

As the number of clinical trials for CGTs proliferates, sponsors may want to reconsider how they approach the possibility that a study could—or should—be placed on clinical hold. A proactive and collaborative mindset may prove beneficial. For example, sponsors could proactively plan for a clinical hold in the trial timeline. Likewise, they could include the concept of a clinical hold—along with some context—in their patient-facing and family-facing study information. Sponsors could note that a clinical hold is a common measure taken in these drug development programs, and that it reflects careful and continuous oversight of the well-being of every participant.

Clinical holds don’t necessarily indicate gene therapies are unsafe but that the industry is developing them thoughtfully and carefully. There is value in truly examining every meaningful event with every patient. By encouraging an abundance of caution, clinical holds can help promote confidence in the groundbreaking therapies that come out the other end of the pipeline.

Improving efficiency with innovative designs

Today nearly 80% of gene therapy products in clinical development are for the treatment of rare diseases or cancers.13 These are complex programs, many with inherent recruitment challenges, which unfortunately can extend timelines. While every corner of clinical development could benefit from increased efficiency, CGT programs serving rare disease and oncology patient communities have some of the most pressing needs.

Fortunately, recent years have seen notable progress in master protocols, specifically in the areas of rare diseases, pediatrics, and precision oncology.14,15,16,17 These master protocols, which include basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies. Basket trials, for example, test a single treatment in several different patient populations simultaneously, and have become rather commonplace in the development of precision anticancer treatments. Conversely, umbrella trials enable simultaneous testing of multiple versions of a given product in a single patient population.

In other words, several potential treatments for one disease are tested directly against each other in umbrella trials. By uncovering which versions of a treatment in development are the most promising, the use of umbrella trials in early-phase clinical trials has the potential to decrease development time and increase the odds of an ultimately successful product.

However, umbrella trials remain somewhat underutilized despite the value they can bring to product development.18 In part, that is because they are tricky to design in a way that enables confident submission and interpretation. They require carefully crafted master protocols—as well as a different mindset regarding protocol creation.

In nearly any other setting, specificity is the aim of protocol writing. The more specific the protocol, the better for quality assurance and data interpretability. But that deeply ingrained wisdom must be selectively set aside to construct an effective master protocol.

Master protocols may seem more daunting to write because they must strike a delicate balance between specificity and flexibility. It’s important to know where the protocol needs to provide space instead of tight confines, so those elements can be written in a way that offers the freedom to operate each arm of the trial as necessary.

Think of a master protocol like a Mad Libs® game in which you don’t know exactly which adverbs to use, but you know that adverbs are needed. Likewise, when sponsors begin to develop the protocol and IND submission package, they may not know precisely which variants they’ll pursue within the various arms of a study. Still, they’ll want to know what kinds of elements may mark one variant from another. That is where to build in flexibility, so each variant can be included per the exact language of the master protocol. Rather than describe each variant precisely, the master protocol should employ intentionally flexible language for aspects related to how product variants differ from one another. It is the lack of flexibility on these topics that leads to the inefficiency of amendments.

Source: Worldwide Clinical Trials

Source: Worldwide Clinical Trials

With that thought in mind, consider these two best practices for thoughtfully writing master protocols for early-phase CGT umbrella trials:

  1. Come to a firm conclusion about how many variants will be studied, prior to the first IND submission.
  2. Decide what will differentiate the variants from one another.

The answers to those two questions will guide where to create flexibility in the master protocol. In addition, FDA recently released its own timely guidance to help sponsors conduct early-stage umbrella trials for cell and gene therapies.

Key takeaways: FDA guidance

With the increasing number of cell and gene therapies on the horizon, FDA’s recent guidance on studying multiple versions of a cell or gene therapy product comes at an opportune moment.19 It sheds light on the agency’s recommendations to help sponsors achieve value by creating rigorous early-phase umbrella trials that could result in faster, more efficient cell and gene therapy development.

While the guidance itself isn’t lengthy—eight pages plus a two-page appendix—it offers sponsors several key takeaways, including recommendations about:

IND numbers. As FDA outlines, the primary IND using an umbrella approach is no different from a regular IND. Primary INDs include clinical information about the umbrella trial, while secondary INDs do not. However, FDA suggests that sponsors request preassigned IND numbers for the primary and all secondary INDs. The agency takes its recommendation further by advising sponsors to clearly state in each cover letter whether an IND is primary or secondary, then cross-reference all the numbers for the other INDs that support the study. In other words, they’d like sponsors to group everything together from the very beginning.

That means sponsors would have to know upfront how many secondary IND numbers they want. It’s a “measure twice, cut once” scenario. While it’s not impossible for sponsors to change their minds about the number of product versions they ultimately want to test, it would unnecessarily complicate matters. Sponsors would either be left with numbers that don't correspond to an actual secondary IND or unaligned numbers. So, the sooner sponsors nail down how many versions of the product they wish to include in an umbrella trial, the better for all stakeholders involved.

Clinical holds. It’s worth knowing that a clinical hold in an early-phase CGT umbrella trial may not affect the whole program. Clinical holds may be placed either on the entire program—meaning all arms of the study—or just a single arm. Conceivably, even a clinical hold caused by a potential safety concern could primarily affect just one arm (if the problem doesn’t apply to all product versions).

Adverse events. It’s also worth noting that the guidance offers a mechanism to ensure adverse events in an umbrella trial aren’t overcounted. While sponsors must submit safety reports for all relevant primary and secondary INDs, FDA recommends that they clearly identify reports submitted to secondary INDs as “duplicates” so that the same adverse event is not counted more than once.

Innovative mindsets, innovative therapies

It is an exciting time in the evolution of cell and gene therapies. We have only begun to tap their ability to create substantial clinical benefits. Inevitably, however, innovations of this magnitude require us to step back and take a fresh, more holistic look at the clinical trial landscape.

Given the small and typically vulnerable patient populations often involved in cell and gene therapy studies, it’s clear we must redefine the concepts of risk and value. Such therapies are “high-reward” because of their potential to treat—or even cure—disease, but thus are also high-risk. So, clinical holds must be valued more for the responsible safeguards that they are. At the same time, umbrella trials should be embraced for their capacity to uncover the most auspicious treatments faster and more efficiently. It’s energizing to think about what altering our mindsets could mean for clinical trial speed, efficiency, and the ability to pursue treatments that truly hold the most promise for patients.

Amy Raymond, PhD, PMP, senior director, therapeutic strategy lead, rare disease, Worldwide Clinical Trials


  1. U.S. Food and Drug Administration. “FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions.” 17 Aug 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who
  2. U.S. Food and Drug Administration. “FDA Approves First Gene Therapy to Treat Adults with Hemophilia B.” 22 Nov 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b
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  9. Business Wire. “Graphite Bio Announces Voluntary Pause of Phase 1/2 CEDAR Study of nulabeglogene autogedtemcel (nula-cel) for Sickle Cell Disease.” 05 Jan 2023. https://www.businesswire.com/news/home/20230105005859/en/Graphite-Bio-Announces-Voluntary-Pause-of-Phase-12-CEDAR-Study-of-nulabeglogene-autogedtemcel-nula-cel-for-Sickle-Cell-Disease
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