Science? We don't need no stinkin' science!

[George K]

Top FDA official overrules staff to approve gene therapy that failed trial

The Food and Drug Administration (FDA) on Thursday announced expanded approval for a gene therapy to treat Duchenne muscular dystrophy (DMD)—despite the fact that it failed a Phase III clinical trial last year and that the approval came over the objections of three of FDA's own expert review teams and two of its directors.

In fact, the decision to expand the approval of the therapy—called Elevidys (delandistrogene moxeparvovec-rokl)—appears to have been decided almost entirely by Peter Marks, Director of the FDA's Center for Biologics Evaluation and Research.

Elevidys initially gained an FDA approval last year, also over objections from staff. The therapy intravenously delivers a transgene that codes for select portions of a protein called dystrophin in healthy muscle cells; the protein is mutated in patients with DMD. Last year's initial approval occurred under an accelerated approval process and was only for use in DMD patients ages 4 and 5 who are able to walk. In the actions Thursday, the FDA granted a traditional approval for the therapy and opened access to DMD patients of all ages, regardless of ambulatory status.

"Today’s approval broadens the spectrum of patients with Duchenne muscular dystrophy eligible for this therapy, helping to address the ongoing, urgent treatment need for patients with this devastating and life-threatening disease," Marks said in the announcement Thursday. "We remain steadfast in our commitment to help advance safe and effective treatments for patients who desperately need them."

In a blog post Friday, a notable pharmaceutical industry expert and commentator, Derek Lowe, admonished the approval. Lowe expressed concern that the agency seems to be tilting toward emotional rhetoric and the will of patient advocates over scientific and medical evidence.

"It appears that all you need is a friend high up in the agency and your clinical failures just aren't an issue any more," he wrote. "Review committees aren't convinced? Statisticians don't buy your arguments? Who cares! Peter Marks is here to deliver hot, steaming takeout containers full of Hope. ... And while I realize that this may make me sound like a heartless SOB, I think this is a huge mistake that we will be paying for for a long time."

In a comment to Stat News, former FDA chief scientist Luciana Borio echoed concerns about how decisions like this will affect the agency in the longer term.

"I don’t know what to say. Peter Marks makes a mockery of scientific reasoning and approval standards that have served patients well over decades," said Borio, who has also opposed earlier controversial approvals. "This type of action also promotes the growing mistrust in scientific institutions like the FDA."

In a memo of his own, Marks agreed that primary endpoint result of the trial—based on scores on a standardized assessment of motor function in patients—did not show a statistically significant benefit. But he argued that the secondary endpoints were convincing enough for him.

[Jolly]

I AM SCIENCE!l

Well, I guess they found another one...

[LuFins Dad]

The therapy intravenously delivers a transgene

I knew it! Kennedy is right!

[Jolly]

@LuFins-Dad said in Science? We don't need no stinkin' science!:

The therapy intravenously delivers a transgene

I knew it! Kennedy is right!

Saw where Kenbedy just missed the numbers for the CNN debate.

Wouldn't that have been fun?

[Axtremus]

Will more harm be done to the patients undergoing this therapy given the expanded approval? Or is this just a matter of the therapy not delivering (statistically significant) enough benefits?

Is there a reason the FDA rules allow one director to override objections from three reviewers and two other directors? Would you rather that there be absolute rules on the FDA goes by majorities among the reviewers and directors?

[George K]

@Axtremus said in Science? We don't need no stinkin' science!:

Will more harm be done to the patients undergoing this therapy given the expanded approval?

I dunno. Will patients not benefit from other therapies that might be withheld?

Or is this just a matter of the therapy not delivering (statistically significant) enough benefits?

In the distant past, hydroxychloroquine and other medications in the distant past were shown to not deliver statistically significant benefit.

Is there a reason the FDA rules allow one director to override objections from three reviewers and two other directors? Would you rather that there be absolute rules on the FDA goes by majorities among the reviewers and directors?

Yeah, I'm not down with one person permitting the approval of the drug because of the feelz.

[Axtremus]

@George-K said in Science? We don't need no stinkin' science!:

@Axtremus said in Science? We don't need no stinkin' science!:

Will more harm be done to the patients undergoing this therapy given the expanded approval?

I dunno. Will patients not benefit from other therapies that might be withheld?

FDA approval is not a zero-sum game, the FDA can approve unlimited number of drugs and therapies. Actual prescription and payment for drugs/therapies may be a zero-sum game. But that comes down to the physician prescribing the drugs/prescriptions, whether the physician is knowledgeable enough to prescribe the more beneficial ones over the less beneficial ones.

[George K]

@Axtremus said in Science? We don't need no stinkin' science!:

FDA approval is not a zero-sum game

You missed my point. It's not a question of zero-sum, it's a question of "Since you're already on Drug A, perhaps we should hold off on trying Drug B until we see how it works."

[Mik]

I think we'd need to know what those secondary endpoints were. Perhaps I will run this by my BIL who was the chief statistical analyst for a large pharma firm.

[Axtremus]

@George-K said in Science? We don't need no stinkin' science!:

@Axtremus said in Science? We don't need no stinkin' science!:

FDA approval is not a zero-sum game

You missed my point. It's not a question of zero-sum, it's a question of "Since you're already on Drug A, perhaps we should hold off on trying Drug B until we see how it works."

I addressed that point, essentially saying that’s on the prescribing physician, not on the FDA.

[Axtremus]

@Mik said in Science? We don't need no stinkin' science!:

I think we'd need to know what those secondary endpoints were. Perhaps I will run this by my BIL who was the chief statistical analyst for a large pharma firm.

Hmmm …. big pharma guy may have a bias for the FDA to approve stuff more liberally; can we trust him?

[jon-nyc]

I saw it yesterday and was heartened by the news. I’ve been in meetings with him where he said he’d issue guidance on clinical trial endpoints just to be later scuttled by his staff for rather dubious reasons. I could give details if anyone is interested.

I don’t know the details of the Duchenne drug but, knowing him, there’s no way it’s as simple as ‘feels’. There’s probably a small signal and knowing it will help at least some boys destined to become cripples to stave it off a bit is not a bad thing IMO.

There’s some new legislation in the senate being pushed by Braun (R-IN) and Gilibrand (D-NY) that would allow ultra-accelerated approvals (post P1!) for certain ultra-rare conditions providing the patients become part of a registry so they can figure out quickly if it’s working.

[jon-nyc]

@Mik said in Science? We don't need no stinkin' science!:

I think we'd need to know what those secondary endpoints were. Perhaps I will run this by my BIL who was the chief statistical analyst for a large pharma firm.

Primary endpoint was a 18 point motor skill test. Secondary was the ability to stand and walk. Non trivial if it’s your son.

Also the expanded approval is provisional and they’re requiring a confirmatory study.

More here. https://endpts.com/fda-widens-sareptas-duchenne-gene-therapy-to-older-boys-in-significant-expansion-of-use/

[Mik]

@Axtremus said in Science? We don't need no stinkin' science!:

@Mik said in Science? We don't need no stinkin' science!:

I think we'd need to know what those secondary endpoints were. Perhaps I will run this by my BIL who was the chief statistical analyst for a large pharma firm.

Hmmm …. big pharma guy may have a bias for the FDA to approve stuff more liberally; can we trust him?

You have no idea of the ethical standards our pharma firms adhere to. If you did you'd be impressed.

[Mik]

@jon-nyc said in Science? We don't need no stinkin' science!:

@Mik said in Science? We don't need no stinkin' science!:

I think we'd need to know what those secondary endpoints were. Perhaps I will run this by my BIL who was the chief statistical analyst for a large pharma firm.

Primary endpoint was a 18 point motor skill test. Secondary was the ability to stand and walk. Non trivial if it’s your son.

Also the expanded approval is provisional and they’re requiring a confirmatory study.

More here. https://endpts.com/fda-widens-sareptas-duchenne-gene-therapy-to-older-boys-in-significant-expansion-of-use/

Not trivial at all. This is a tempest in a teapot. IMO there was good reason for the approval.

[Mik]

There comes a point where you have to delve deeper into what 'do no harm' really means. Perhaps allow no harm might be included. In the cases of hopeless diseases with assured catastrophic outcomes it is hard to imagine you could do much harm with a drug that had made it through phase three trials, even if the benefit is less than what you hoped.

[George K]

@jon-nyc said in Science? We don't need no stinkin' science!:

I saw it yesterday and was heartened by the news. I’ve been in meetings with him where he said he’d issue guidance on clinical trial endpoints just to be later scuttled by his staff for rather dubious reasons. I could give details if anyone is interested.

I don’t know the details of the Duchenne drug but, knowing him, there’s no way it’s as simple as ‘feels’. There’s probably a small signal and knowing it will help at least some boys destined to become cripples to stave it off a bit is not a bad thing IMO.

There’s some new legislation in the senate being pushed by Braun (R-IN) and Gilibrand (D-NY) that would allow ultra-accelerated approvals (post P1!) for certain ultra-rare conditions providing the patients become part of a registry so they can figure out quickly if it’s working.

Interesting take, thanks.

[Jolly]

@jon-nyc said in Science? We don't need no stinkin' science!:

I saw it yesterday and was heartened by the news. I’ve been in meetings with him where he said he’d issue guidance on clinical trial endpoints just to be later scuttled by his staff for rather dubious reasons. I could give details if anyone is interested.

I don’t know the details of the Duchenne drug but, knowing him, there’s no way it’s as simple as ‘feels’. There’s probably a small signal and knowing it will help at least some boys destined to become cripples to stave it off a bit is not a bad thing IMO.

There’s some new legislation in the senate being pushed by Braun (R-IN) and Gilibrand (D-NY) that would allow ultra-accelerated approvals (post P1!) for certain ultra-rare conditions providing the patients become part of a registry so they can figure out quickly if it’s working.

All for it. The FDA had become a bureaucratic bunch of assholes, at least at the far end of the stream that I traipsed through.

Case in point...Europe had HIV and Hepatitis C tests on the market from major manufacturers (Abbott, etc.) months and even years before we did.

The fast-tracking of drugs and testing during COVID showed us that on some things, we were waaay too cautious.

[Axtremus]

OK, now that it looks like @jon-nyc’s post turned the tide of opinions, let’s take a look at the opposing side.

What are the reasons and motivations of the three reviewers and two FDA directors to have opposed approval? Any conflict of interest or ideological bias that we need to look into? What makes “notable pharmaceutical industry expert and commentator, Derek Lowe” admonish the approval? Does Derek Lowe know what he’s talking about? Do those three reviewers and two FDA directors know what they are doing?

Is it good that FDA rules allow for a single director to override three reviewers and two other directors now?