Experts outline considerations for pivotal trial designs for new CGTs
As cell and gene therapies (CGTs) continue to advance, they have unique developmental features that may require innovation in a clinical trial setting, the authors of a recent paper explained.
Patricia Anderson, director of biostatistics consulting at ICON Plc, and her co-authors, which included staff from the Center for Biologics Evaluation and Research at the US Food and Drug Administration (FDA) and members of industry, said FDA approved initially approved CGTs because of small population sizes, unmet medical need, and a treatment effect that was “substantial compared with knowledge about the natural history of the disease.”
At the same time, new CGTs have “unique challenges compared with the first-generation products, particularly as those first-generation products are becoming the standard of care,” they said. The evaluation of newer CGTs raises questions about whether they should be compared in pivotal trials with already approved CGTs, whether the standards for effectiveness could be met, and if there is still a path for single-arm trials for new products.
In a conventional randomized controlled trial (RCT) setting, new CGT candidates could be evaluated against both existing CGT and non-CGT therapies, and evidence has shown “very strong effects” for primary and secondary outcomes like survival, disease progression, and durable response rate. However, it may bring about ethical issues if a non-CGT treatment is required as standard of care in countries where CGTs for a given condition have already been approved.
A superiority or a non-inferiority design may be better suited for some situations, but the authors acknowledged that each therapy carries its own set of challenges with regard to efficacy, low disease incidence and prevalence, manufacturing, cost, and randomization for products that require coordinating manufacturing slots.
The authors noted that, to demonstrate clinical superiority over another therapy, there would be a need to conduct a study with a large sample size to establish adequate power. To randomize patients, the clinical trial enrollment would need to consider manufacturing capacity and availability for intervention and control arms. In addition, patients in each arm would need to be treated at the same time.
“Addressing these challenges through innovative design and analysis strategies is essential,” Anderson and colleagues said.
Hybrid trial designs
Anderson and colleagues proposed a prospective-randomized hybrid trial for evaluating two different CGTs with a flexible design as one alternative approach. Under this approach, patients are randomized to a single arm for either an intervention or existing CGT that generates real-world data. If the trial is evaluating efficacy between arms, real-world data collected during the trial in the existing CGT arm can be used to determine the treatment effect between groups, the authors said.
However, a prospective-randomized hybrid approach may not address issues such as requiring insurance coverage of patients, patients wanting to be randomized to the already approved treatment, and considerations involving crossover therapy if deemed safe and appropriate by clinicians, they noted.
Another potential approach could be a control augmented hybrid design that randomizes most patients to the intervention and uses control data from real-world or other external sources, the authors said. They noted this approach may encounter manufacturing issues, and assumes equality among patients in a trial control group and real-world data.
“[W]e recommend that trialists carefully consider the objectives of the study regarding the potential benefits and advantages of the experimental product within the current treatment landscape, when designing their intended studies,” Anderson and colleagues said. “When proposing hybrid designs, proactive and frequent communication among all stakeholders, including regulators, sponsors, and payers, is essential to achieve alignment of their operational and scientific features and implementation.”
The authors also proposed that the use of single-arm trials for new CGTs may still play a role in the future, particularly for ultra rare diseases. In single arm trial designs, patients may also be able to serve as their own control group. Across all clinical trial designs, the central focus of defining a clinical question of interest remains critical, they noted.
“The future opportunity of cell and gene therapy is bright, and it will take a collaborative community working together to bring them from bench to bedside around the globe,” the authors said.
“To navigate and overcome the challenges facing pivotal clinical trials of CGTs, more dialogue between all stakeholders and strong collaboration across academia, industry, regulators, payers, physicians and patients to find solutions is highly encouraged,” they concluded.
