The status could support staged transitions to new manufacturing processes, potentially mitigating some risks of high-stakes switches.
Cell and gene therapy experts agree it is optimal to pick a manufacturing platform in preclinical and keep using it as a candidate advances through human trials and to the market. Yet that advice is of little use to sponsors who learn after trials are underway that their processes aren’t as scalable as they’d believed. Those companies have faced the prospect of landing themselves in a regulatory thicket in trying to get the green light for a switch. But that may be changing—at least for those sponsors who’ve secured an Advanced Manufacturing Technology (AMT) designation from the FDA.
The challenges faced by manufacturers of approved cell and gene therapies, many of which fail to achieve commercial success, show the risks of coming to market with a suboptimal production process. Manufacturing processes that work well enough for small, early phase trials can suffer from inefficiencies that make it hard to achieve commercial viability. Seeking to launch with scalable processes that enable profitable production at a price that is appealing to payers, companies may be tempted to rethink manufacturing between entering the clinic and winning approval.
Switching brings risks, though. Don Fink, a regulatory expert at Dark Horse Consulting, told BioSpace it is simplest to adopt technologies before a candidate enters clinical trials. By using a technology from the start of development, companies can build chemistry, manufacturing and control strategies around it from day one. Anna McMahon, director of regulatory affairs at cell therapy manufacturer Cellares, agreed, telling BioSpace that the optimal time to settle on a process is before a company files an IND to study a treatment in humans.
Fink said switching manufacturing platforms mid-development poses unique challenges. A sponsor that has generated early-phase data and is moving toward a larger efficacy trial will need to show that products made using the old and new manufacturing platforms are comparable. Fink said making comparisons without the baseline of an approved drug is problematic from a regulatory perspective.
The later a sponsor waits before making a change, the harder it is to manage the transition, according to the consultant. That means spending more time and money on the switch, Fink said, “and time and money in this day and age are pretty critical to whether or not you’re going to succeed.”
Yet these risk calculations may be evolving. Encouraged by the opportunities created by the FDA’s launch of its AMT program, McMahon said sponsors now have a blueprint for how to change manufacturing technologies while keeping their R&D programs on track.
Changing the Risk Equation
McMahon, whose company won an AMT designation for its platform in April and has had talks with the FDA under its auspices, is more bullish than Fink on the options available to companies that miss the optimal, pre-IND window. AMT designations give users of technologies that substantially improve manufacturing processes more opportunities to engage with the FDA, potentially smoothing the switch to technologies that have the status.
According to McMahon, the AMT designation “fundamentally changes the risk equation for cell therapy developers” and provides “a clear, repeatable path to engage FDA on manufacturing early.” Regulators understand switching manufacturing platforms is a complex change, she said. The FDA’s guidance on AMTs says that drug developers using designated technologies will benefit from additional communication “during both early drug development and subsequent application assessment.”
Through the AMT framework, the FDA is allowing “staged, evidence-led transitions” rather than viewing platform switching as all-or-nothing, McMahon said. The framework thus allows mid-trial switches to AMT-designated manufacturing platforms to be executed without interrupting studies, the Cellares director explained.
McMahon named multiple ways companies can use AMT designations to support transitions. She advised sponsors to validate comparability in parallel with ongoing trials using the designated platform by running side-by-side lots with pre-agreed readouts while dosing continues. She also recommended maintaining clinical continuity through bridging strategies that are discussed in advance with regulators to keep dosing on schedule.
Sponsors can use AMT-specific interactions to align on acceptance criteria before manufacturing clinical material, McMahon said. The interactions also offer chances to “plan future phases with confidence in the manufacturing foundation, including identity controls and data expectations.”
“This keeps trials on schedule and sets up a process that can be repeated across sites after approval,” McMahon added.
The short history of the AMT program, which the FDA finalized in January, means Cellares, Oribiotech and the other companies with designations are still determining the impact of the regulatory status. While the scientific challenge of proving comparability will remain, the AMT program may offer a way to simplify the regulatory path, McMahon said.
Whether companies are willing to take that path and what happens to those that do may become clearer over time. For now, the program at least offers a potential way forward for sponsors that fear they may risk future commercial failure by coming to market with a costly, unscalable process.
