Accelerated approval is likely to be used more extensively in the future for gene therapies that treat very rare diseases, but the slowly progressive nature of some conditions means there may be many years of uncertainty about the clinical benefits provided by the one-time treatments, the head of the US FDA’s Office of Tissues and Advanced Therapies said.
OTAT Director Wilson Bryan opined on the future use of accelerated approval for gene therapies, worries about ambiguous confirmatory trial results that come in years after approval, and the agency’s willingness to withdraw a product for failing to verify clinical benefit during the 13 February Prevision Policy/Friends of Cancer Research Biopharma Congress.
Bryan is retiring from the agency by the end of March. (Also see “FDA’s Cell, Gene Therapy Office Head Wilson Bryan Set To Retire” – Pink Sheet, 30 Jan, 2023.) He will be replaced on an acting basis by Center for Biologics Evaluation and Research Deputy Director Celia Witten. (Also see “The Risk-Reward Of US FDA Leadership Running Offices Below Them” – Pink Sheet, 9 Feb, 2023.)
“We’re going to get into trouble, I’m worried, with accelerated approval in gene therapies. If it takes years as suggested to tell if something works, then that means it takes years to tell if it doesn’t.” – FDA’s Wilson Bryan
He was asked why accelerated approval would ever be considered for a one-time curative gene therapy given that the product would be expected to have dramatic efficacy.
The OTAT director said he liked using the term “curative” because often sponsors will assert their product is going to have an incremental effect on a disease.
“We need to be having drugs that have dramatic changes that really make a difference in people’s lives,” Bryan said. “And fortunately the science, and particularly in gene therapy, but with other areas too, it allows us to do that in some cases.”
“In cell and gene therapy, I like that we talk about cures,” Bryan added. “Now whether any of these products actually cures is a separate question.”
“If we had a true curative therapy, is it possible that you wouldn’t be able to see it for several years?” Bryan said. “Some of these diseases are so slowly progressing that it may be difficult, and we will have to rely on biomarkers. I want to say that I think that those diseases are relatively few, and that if a product truly has dramatic effects in most cases we’ll be able to see something clearly in a year or two.”
Waiting Years to See If Something Doesn’t Work
However, Bryan also said “we’re going to get into trouble, I’m worried, with accelerated approval in gene therapies. If it takes years as suggested to tell if something works, then that means it takes years to tell if it doesn’t.”
He referenced the agency’s September 2022 accelerated approval of bluebird bio’s gene therapy Skysona (elivaldogene autotemcel) for boys with early, active cerebral adrenoleukodystrophy (CALD). (Also see “Accelerated Approval For Bluebird’s Skysona Gives Teeth To US FDA Data Questions” – Pink Sheet, 19 Sep, 2022.) The agency’s use of the expedited pathway came as a surprise given that it was not mentioned at an advisory committee review of the product three months earlier. (Also see “Bluebird’s Eli-Cel Gene Therapy Gets US Panel Nod For Some Cerebral Adrenoleukodystrophy Patients” – Pink Sheet, 9 Jun, 2022.)
The FDA imposed two postmarketing study requirements to verify Skysona’s clinical benefit: 10-year follow-up assessing event-free survival in patients treated in two ongoing, single-arm trials; and five-year event-free survival in 24 newly treated boys with more advanced, early active CALD. The final study reports are due in July 2032 and December 2038, respectively.
The confirmatory evidence is going to take five or 10 years, “and that presumes that the confirmatory evidence is clean enough that we can tell it works,” Bryan said of Skysona.
If those postmarketing studies suggest the gene therapy does not work, “or we still can’t tell if it works or not, what has happened to that field? … It’s just been sitting around waiting, because the patients that are getting the gene therapy in a very rare disease, you’re cutting down the population that’s available for the next product. And will somebody else develop the product?” Bryan asked.
“So I really worry that the damage … by approving something under accelerated approval is, at the end of the day, does it work?” he said.
Although this will be a problem for gene therapies where effects are not seen until far down the line, “I don’t know that there’s anything we can do about that,” Bryan said. “I expect that accelerated approval will be used more and more frequently in gene therapy and cell therapy, but the confirmatory studies are going to take awhile in some cases, and that’s going to be a problem.”
“I worry that some drug companies have an interest in having their confirmatory study be, shall we say, ambiguous and uninterpretable, and you can say whatever you want and then it makes it very difficult for the agency to take something away.” – FDA’s Wilson Bryan
Bryan raised particular concern about lingering uncertainty regarding clinical benefit even after the postmarketing studies are completed.
While there is an expectation that some accelerated approval drugs will fail to confirm clinical benefit and have to come off the market, “there’s a presumption there that we can tell when we made a mistake, and I’m not sure that we’re going to be that good at telling,” Bryan said.
“I worry that some drug companies have an interest in having their confirmatory study be, shall we say, ambiguous and uninterpretable, and you can say whatever you want and then it makes it very difficult for the agency to take something away,” he added.
“And does the agency have the willpower to say, okay, the data is ambiguous, it looks like it probably doesn’t work, I’m not sure it doesn’t work, but let’s take it off the market in this rare disease with no treatment available?” Bryan asked. “I’m not sure the agency has the will to do that. So we’re going to have some very difficult situations.”
“It’s really unfortunate because … in the setting of cell and gene therapy, you’re making a one-time decision to take a product, and you want to believe with the backing of the FDA that this thing really works. And the FDA doesn’t know and you don’t know,” Bryan said.
Although Bryan conceded to sounding pessimistic, he insisted he is, in fact, an optimist who believes in the science.
“The science moves forward and gets us through these problems, and the science will work this out,” he said. “It’s just we have to follow the science and not get ahead of the science.”
Hitting The ‘Sweet Spot’
During another conference session, CBER Director Peter Marks also weighed in on the difficult balance between taking a regulatory risk in granting accelerated approval to make new therapies available sooner and being willing to withdraw a product when the hoped-for benefits do not pan out.
“I think accelerated approval is something that we have to make sure everyone hates, because if everyone hates it we’ve got it right,” Marks said to laughter in the room. “And that means that those who think we’re doing it too fast, and those who think we’re doing it too slow. So if everyone hates where we’re doing it, it means we’ve got it right in the sweet spot in the middle.”
“We don’t want products to be out there that have such dubious efficacy that insurers say we’re not going to cover this … because that doesn’t help the public either.” – FDA’s Peter Marks
If the agency waits until the evidence is very clear on an efficacy endpoint, “then you might as well just go ahead and give things your traditional approval,” he said, adding that this is why many of the CAR-T products received regular approvals.
“On the other hand, we don’t want products to be out there that have such dubious efficacy that insurers say we’re not going to cover this … because that doesn’t help the public either,” Marks said.
He did not specifically call out the Center for Drug Evaluation and Research’s still-controversial accelerated approval of Biogen, Inc.’s Alzheimer’s drug Aduhelm (aducanumab-avwa), which has led to a national coverage decision strictly limiting Medicare reimbursement for all amyloid-directed antibodies in Alzheimer’s disease.
“We have to find a sweet spot that there’s enough evidence that we feel that … we can with a straight face say that the surrogate we’ve used was reasonably likely to predict, and we have confidence in that,” Marks said.
Like other senior FDA officials, Marks said that if 100% of its accelerated approvals ultimately confirmed clinical benefit, the evidentiary bar would be too conservative. However, “you don’t want to be pulling everything you approve.”
“And it’s painful, right? Everyone hates it,” Marks said. “Again, when we’re fully hated, we’re doing our jobs. … We sometimes will have to pull things from the market, but that’s okay. Because it does mean that we will not prevent something from getting there that could help people that have a terrible disease and ultimately save lives.”
