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Posted 17 May 2022 | By Joanne S. Eglovitch 

FDA, EMA officials discuss impediments to cell and gene therapies

2831 The US Food and Drug Administration’s (FDA) top biologics regulator said the use of a  “playbook” or platform approach for developing multiple cell and gene therapy products and a globally harmonized template would facilitate the development of such products at a 17 May meeting of the American Society of Gene and Cell Therapy (ASGCT).
Peter Marks, the director of the FDA’s Center for Biologics Evaluation and Research (CBER) and Ana Hidalgo-Simon, head of advanced therapies at the European Medicines Agency (EMA), also agreed that manufacturing and reimbursement challenges are impeding the development of these products.
At the meeting, the regulators were asked to address why there have not been more approvals of these products, and their suggestions for ushering more of these therapies to market.
Why slowdown
Moderator Keith Wonnacott of Lexeo Therapeutics asked the panelists to address the limited growth in this segment in recent years.
He said, “In 2017 and 2018 there was a lot of excitement and we thought there would be massive growth for approvals of cell and gene therapies, yet in the last year or two we have seen examples of several products that were unsuccessful for various reasons.”
Marks responded, stating that “manufacturing clearly has been the weak link here, and unfortunately sometimes we have gotten into these loops where products that we studied very early on were different from the product that we studied later on, or had different comparability. That has led to some hiccups in their development.”
There have also been issues with setting correct clinical endpoints in terms of “what are you measuring,” he said.

Hidalgo said that she “absolutely agreed” with Marks’ assessment on these challenges. She added that another impediment postapproval is having these products denied reimbursement through Europe’s healthcare technology assessment (HTA) bodies.
Marks agreed that reimbursement issues are “the 800-pound gorilla in the room.” He added that “it is a little disconcerting that with each new entity it’s the value proposition … for Zolgensma, the value proposition is so overwhelming that it is hard not to think of not covering that, whereas for other gene therapies where it is not a life-or-death issue, it may be more challenging and will be in a similar situation as our European colleagues with people thinking about healthcare cost savings, so this is something that we have to pay attention to."
‘Cookbook’ approach would spur uptake
Regulators were asked to discuss some possible solutions for these challenges.
Marks said that sponsors need more financial incentives to develop cell and gene therapies for small populations. He added that the newly launched Bespoke Gene Therapy Consortium, part of the NIH Accelerating Medicines Partnership (AMP) program, which aims to optimize and streamline the gene therapy development process to help fill the unmet medical needs of patients with rare diseases, is developing such a “playbook” or a “cookbook” for these products.
Once this playbook is finished it would be made available to academic centers and small entities that develop these therapies; the approach would allow certain manufacturing technologies and processes to be combined.
Such an approach would make it more “commercially viable” for manufacturers to produce small batches of these therapies.
Marks said that many of these therapies only treat 20 to 40 individuals per year, and may not be commercially viable for many sponsors, and that such a playbook would make it more feasible to manufacture these products.
Marks added that greater regulatory harmonization would also help spur the development of these therapies.
“If you have a product that is designed to treat a population of 10 or 20 or 100 people, you do not have a sufficient number of patients to sustain commercialization, but once it gets gets to a more global perspective, one can see its continued sustainability.”
Agreement on surrogate endpoints
Regulators were also asked to comment on whether the accelerated approvals pathway is a viable pathway for these products if there is not agreement on surrogate endpoints upfront in the development process.  
Wonnacott said, “It seems like a lot of accelerated approvals that I’m aware of happen in a setting where FDA did not agree to the surrogate endpoint as producing the clinical benefit before the trial started but after the trial is over, they allowed it.”
Marks said that there should be greater agreement on the use of surrogates up front before this pathway is used. He added that the accelerated approvals pathway “has been used as an off ramp for problems in the past … I do think that is a point where we should be talking up front about where surrogates should be used and to discuss this in development programs. Being able to use a surrogate endpoint might mean the difference between having a therapy or not or allowing the therapy to be expedited.”
He added that upfront agreement on surrogate endpoints would help avoid surprises, adding that “surprises are not needed in this field.”
Stakeholder survey
Marks was also asked to comment on the findings of a recent survey of stakeholders on reviews of cell and gene therapies.
The major complaint among stakeholders was the “need for consistency and timeliness” of reviews. Marks said that stakeholders found it “highly problematic” when reviewers arrived at two different conclusions for products using similar manufacturing process.
Another common complaint was lack of timely communications with sponsors.
ASGCT annual meeting


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