Sarepta. Why? | Hacker News Reader

Sarepta. Why?

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98 pointsrossdavidh91 comments

"The agency has just granted that use expansion, and it turns out that it was all due to Peter Marks, who completely overruled three review teams and two of his highest-level staffers (all of whom said that Sarepta had not proven its case)."

It's sad when drugs are sold on hope and not on science. This reminds me of Biogen's Alzheimer's drug that eventually was stopped after millions were spent by people hoping it would work with controversial clinical results:

https://www.politico.com/news/2024/01/31/biogen-alzheimers-d...

Approved with 40% experiencing liver injury?

Check out the statistical evaluation sections on the study outcomes:

   https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/elevidys

I could see approval override when evidence is marginally positive but impossible to improve (e.g., for lack of study subjects - here ~150 with a rare genetic disease) when the benefit is clear and there is no safety risk (adverse effects - AE).

The primary outcome didn't fail by much in the small sample. It's an assessment scale of physical activity which can be hard to get right and perhaps prone to false negatives for slow responders. So, maybe.

But the liver injury (lots of bad labs) is a significant side effect, as is nausea/vomiting (~50%), fever (~30%), and thrombocytopenia (8%). Even with that, there was no discontinuation d/t AE, because the patients (parents) are so motivated. I'd like to see how quickly patients recovered esp. to normal liver labs, and also understand how whether other gene therapies have shown similar reactions to be transient and benign.

There's probably a lot of variability in immune systems at that age, with possible long-term effects from adverse training. The variability could result in severe problems in a few cases, and the adverse immune training could result in lifelong auto-immune diseases, etc. Which means there's reason for caution.

As for corruption...

Fatalism about corruption is exactly what corrupt regimes nurture, because it passivates objectors and activates collaborators. Please let's not go there.

The FDA process situation now is OK: both staff and advisors are on the record, so any inconsistent top-line decision is clearly discoverable. As far as I can tell, staff and advisory board selection is mostly per scientific skill, albeit with industry representation, and also on the record so that influence can be traced. Above all, reasons are justified and traced to studies on the record, and most marginal approvals (like this one) include post-marketing monitoring to claw back the approval as needed. (My primary objection now is that study data is mostly non-public, and AFAICT there's no requirement to publish negative data).

Picture the situation: someone you love has just been diagnosed with a death sentence disease with no know treatment. The FDA just chose not to outlaw a promising but unproven new treatment for it. Now you get to choose whether to take it or not. And somehow the FDA are evil twisted bad guys!?

Except that the FDA frequently denies treatments lacking evidence of benefit except in these two cases. The real problem is that it costs too much to bring new treatments through a clinical trial

Except that I don't think the FDA should do that? I'm arguing that people should have options that are not certain death.

Not much point researching a better treatment when you can just sell something that doesn't work.

Here's an option: buy cool dude tincture at 10 dollars a bottle instead of this treatment at 10 thousand or whatever.

The point was that people are up in arms about either outcome: FDA denies approval, people get angry. FDA allows approval, people get angry.

> The real problem is that it costs too much to bring new treatments through a clinical trial

As opposed to what? Just letting anything go? We basically have that situation in the alternative medicine world and the grifters are out in full force peddling things that we know don’t work the way they claim. Imagine how bad it would be if we waived away clinical trial requirements.

> The point was that people are up in arms about either outcome: FDA denies approval, people get angry. FDA allows approval, people get angry.

What people want is approval through a fair, orderly process.

If the tests and reports and expert opinions and panel decisions are needed, their results should be respected - for every drug maker.

If the tests and reports &c. aren't needed - they shouldn't be required.

If there's some more nuanced approach required, like experimental exceptions for drugs specifically for people who are otherwise terminally ill, it should be codified.

The approach of "spend a load of money on studies, then maybe the boss ignores the results" seems very open to corruption.

Finding ways to reduce the costs of a clinical trial does not mean abandoning clinical trials (or something sufficiently similar)

At the very least, FDA should allow use of medications that were approved in Japan or the EU.

Requiring separate US clinical trials is an unnecessary burden for the manufacturer, and will likely result in higher prices or unavailability of some medications.

Even in programming we frown upon "reinventing the wheel". This is reinventing the wheel with a fantastic price tag.

The FDA, like other regulatory agencies, exists for a reason: to help prevent people from being ripped off, or worse, by snake oil salesmen. I’d rather we not go back to the days when hucksters and charlatans were selling marked-up dyed water or poison to desperate people out of a horse-drawn carriage.

Completely false comparison because the drug in question did provw safety though the clinical trial, only effectiveness that could not be determined. People should have options that are not certain death.

It’s not a false comparison. Effectiveness is what makes a drug not merely dyed water. Hence the “ripped off” part.

The tricky business is defining effectiveness (and the target population). This drug was not effective at the specified clinical end-point for one set of patients. But it did show promise for other end-points (production of a normal dystrophin transcript).

For complex diseases with a range of severities, failing the specified clinical endpoint is not the same as selling dyed water.

Is production of a normal dystrophin transcript a real clinical endpoint, or just a biomarker that's supposed to correlate for one? It's not immediately obvious how normalizing production of a protein involved in muscle function is beneficial, if it doesn't actually improve muscle function.

Absolutely. But DMD has a spectrum of severities, and it seems possible that for some patients, producing some normal transcript would make a real difference, so that until more people are treated, we cannot know when more normal transcripts make a difference.

Ensuring people have options that aren't certain death is exactly why we care about effectiveness.

Opening up a market for "certain death with extra steps" doesn't address this.

There is a reasonable argument for a regulatory agency to make sure that the peddlers of medication are not selling you something that needlessly will harm you.

There is a weaker but still defensible argument that they should stop others from selling you flu medication that isn't proven to work. But one could imagine a less restrictive reality where such drugs simply must be labeled clearly and you make your own decisions. In fact, there's already a weird carve-out like that for "natural" substances, so you can for example buy artemisinin as a "supplement" if you want to...

But what's the humane argument for "protecting" people with terminal or otherwise devastating diseases from trying drugs that can plausibly work, and were created by people acting in good faith, and that had some clinical trials done, but the trials weren't as thorough as a committee wanted them to?

"Yeah, he died, but at least we stopped him from potentially wasting some money."

I’m going to assume the clinical trial bar exists for a good reason unless proven otherwise. The current system is battle tested at this point and is a significant improvement over the situation that predated the current regulations in terms of safety and efficacy.

And, yes, protecting people - both from being injured and from being ripped off - is a feature of modern society, not a bug.

"I’m going to assume the clinical trial bar exists for a good reason unless proven otherwise."

You cannot, nevertheless, assume that its implementation is absolutely optimal.

There already exists a "Right to Try" exemption for terminally ill patients - precisely what the GP was talking about. https://www.fda.gov/patients/learn-about-expanded-access-and...

It was only introduced in 2018 (federally), so it is a relatively recent development, mostly due to pressure from terminally ill patients and their relatives.

Another thing that is being discussed is that the FDA should allow use of drugs that were approved in other developed countries, without requiring separate clinical trials in the US. American patients aren't that different from British or French patients, after all.

I actually agree with the last paragraph. It does make some sense to have some sort of reciprocity with other trusted nation-states. However, there is obviously going to be some forum shopping as a result, and the country with the lowest bar (as opposed to the highest standards) is going to become the one that bears the lion’s share of the evaluation burden.

If we're going to do this, the nations involved should have a rotation, so that 1/you can't predict which nation is going to get a particular evaluation job and 2/to eliminate the "free rider" problem (which exists today in other contexts, such as unfairly burdening the USA with the majority of Western defense spending).

My city has extensive education and occupational licensing requirements if you want to work at a nail care salon. The assumption that bureaucracies left to their own devices always reach an optimum state and then stop expanding is pretty hard to support.

The FDA had 7,500 employees in the 1990s and 18,000 now. Has the world of food and drug gotten 2.5x more perilous? Or is it possible that, just like in tech, every departmental fiefdom wants more resources and more authority with no special regard for what the trade-offs are?

Another plausible (and less sinister) explanation is that pharmaceutical invention and discovery has accelerated since the 1990s and more applications are being submitted to FDA every year that requires more staff to process them in a timely fashion.

What about the obvious middle position, where the FDA continues to do everything it does and labels drugs as safe and effective, but then theres also non-FDA approved stuff that won't be labeled as FDA approved and you can do it if you want.

The middle of the road solution: let quacks scam desperate people suffering from incurable diseases, as long as the quacks don't put the wrong kind of label on their snake oil bottle.

That’s already established.

It’s called alternative medicine/homeopathy/etc.

That's also deplorable. Herbal supplements too.

If drugs are failing clinical trials, why should they be allowed to be made and consumed at all?

>theres also non-FDA approved stuff that won't be labeled as FDA approved and you can do it if you want.

I assume (even if you didn't realize it) that you mean the $100 Billion plus/year dietary supplements market[0]? That's already (and has been for centuries) in place.

[0] https://www.mordorintelligence.com/industry-reports/dietary-...

There is a nice paper about this question:

> One explanation for drug bans is that regulators know more than consumers about product quality. But why not just communicate the information in their ban, perhaps via a “would have banned” label? Because product labeling is cheap-talk, any small market failure tempts regulators to lie about quality, inducing consumers who suspect such lies to not believe everything they are told. In fact, when regulators expect market failures to result in under-consumption of a drug, and so would not ban it for informed consumers, regulators ex ante prefer to commit to not banning this drug for uninformed consumers.

https://philpapers.org/rec/HANWLA

> The FDA, like other regulatory agencies, exists for a reason: to help prevent people from being ripped off, or worse, by snake oil salesmen.

This is obviously false given the existing supplements business. The idea that we have a way to prevent people from being ripped off is naive. But even so, the "reason" for the FDA doesn't change its incentive structure: allowing a drug that kills a few people will reflect badly on it, while disallowing a drug that would have saved millions of lives likely would have little consequence for the decision makers.

The carve out for supplements was created by Congress in 1994 during the Clinton administration, long after FDA was established, so I don’t think it is a false statement.

https://en.wikipedia.org/wiki/Dietary_Supplement_Health_and_...

IMO, the FDA's authority should be limited to making sure that the snake oil does indeed contain genuine oil from genuine snakes.

They could put a label on it to the effect of "We don't think this stuff works, and it might even be harmful", but they should not be allowed to ban it outright.

The current situation is one-sided:

FDA approves something harmful -> people are harmed and their friends and family start calling for the FDA's heads.

FDA doesn't approve something helpful -> people are also harmed, but most of them don't even know they were harmed. There's little chance of an angry mob showing up at the FDA's door.

The FDA is biased in favor of rejection, not approval.

I don't think being in that situation with a line of snake oil salesmen promising their unproven supposed-cures will help here.

And your loved one dies of the disease at the exact same time they would otherwise have died of it, but now only after having gone through lots of expensive treatment and suffered a bunch of side effects.

The FDA is definitely the evil and twisted bad guys if they can't stop snake oil sellers from stating that their products cure disease X just because the snake oil guy us friends with someone high up in the FDA.

I bet the treatment costs somewhere around $350,000.

These should be approved on the condition that the patients pay into escrow and get refunded one day if the drug fails trials.

Oh no, now I must use my own brain and make the cost-benefit analysis for myself. I wish it was in the hands of some people who neither know nor give a shit about me or my loved one

Desperate parents are well known for their medical expertise and cold logical calculus.

Personally, I think it's egregious to deny people possible treatments, particularly in cases like that. I think FDA should be very strict on approvals (i.e. giving it that stamp), but should not be gatekeeping people. If people want to take non-FDA approved stuff, I don't see why regulatory and/or law enforcement should care. There's an incredible amount of paternalism inherent in the current system that nobody ever seems to question, and that blows my mind.

Now that said, I have a huge problem with this skipping. FDA rules need to be applied consistently and follow the process. I'm sympathetic to the desired outcome, but the problem is the system is set up as a gatekeeper. Fix the system, don't try to hack around it like this. That just further undermines trust and faith in the system.

What’s the best argument you’ve heard against your position about it people taking non-FDA approved stuff?

well, "best" is subjective, but IMHO the best argument against it is that some companies would skip FDA altogether and try to go direct to market, and would use marketing tactics to undermine faith in the FDA and convince people that the lack of FDA approval doesn't matter.

Personally, I do think this would happen, but I think there are better ways to combat this than to use force of law to gatekeep which molecules people are legally allowed to put into their own bodies. We could (and should) still require them to provide evidence for any claims they make, and failure to provide evidence opens them up for liability. There are situations in which paternalism seems justified, but I think in this we've gone way overboard.

AFIAK FDA doesn't regulate what you, yourself, are legally allowed to consume but rather what companies are allowed to market as drugs and legally distribute as such.

For example you can bring your own non-FDA approved drugs with you to the US for personal consumption. I found the following document, section 9-2 covers this topic: https://www.fda.gov/media/71776/download?attachment

That's a fair point, although the FDA (IIUC) has power to say whether some drug must be gated behind a prescription or can be over the counter. For over-the-counter stuff I think you have a good point, but for prescription drugs (which I'm sure is all or nearly all of the interesting drugs) they are gatekeepers.

The argument against it is soaking the health care system for unlimited funds until it collapses or simply becomes unaffordable.

For the horrible things at the edge of treatability and beyond there are always many promising ideas most of them worthless or bad and the price people are willing to pay is either all their money or all everyone's money depending on whether insurance covers it.

If you don't allow insurance to cover it then only a handful of rich folks get soaked but this is politically difficult to maintain.

Insurance already has plenty of leeway to deny coverage for medications, even ones that are FDA approved. If the political unpopularity mattered that much, I'd expect it to already be the case.

Despite the thorny nature of insurance they do already cover lots of things that don't do much good or aren't very efficient. Also medicaid/medicare are more susceptible to political considerations.

> If people want to take non-FDA approved stuff, I don't see why regulatory and/or law enforcement should care.

Well, among other things, if anyone makes money selling colored water, it encourages others to sell colored water. It also encourages companies that are trying to sell actual drugs to skip that expensive "testing" phase. Bad money usually chases out the good (https://en.wikipedia.org/wiki/Gresham's_law) so it's likely that we will devolve into a system where very few drugs are adequately tested.

I'm not saying it never happens, but if a law, policy, or agency reduces big corporation profits, then it's almost always because lots of people were dying.

If so many people were buying non-FDA approved drugs that drug-makers stopped pursuing FDA approval, I think that would be quite indicative that there are some serious issues with the FDA process. At a minimum, that would demonstrate severe system mistrust. Some pressure to improve might be good for them. If the FDA process were bad enough, there would also be a possibility of new standards bodies emerging to provide some third party system. FDA could learn from these and adapt to be better.

I just can't imagine that people would widespread start using drugs that aren't approved though. That's definitely something to watch out for though.

> If so many people were buying non-FDA approved drugs that drug-makers stopped pursuing FDA approval, I think that would be quite indicative that there are some serious issues with the FDA process. At a minimum, that would demonstrate severe system mistrust

Or, it might indicate a financial incentive to get consumers to mistrust a barrier to profit. People in the aggregate are not the most rational actors, in no small part due to information asymmetry. Self interest does not necessarily yield optimal or even good results.

For example, take the new trend of waiving inspections when purchasing homes to outcompete other buyers. This is legally allowed in some places and is getting more common in places where it's a seller's market and there's lots of potential buyers.

Now I'm not so pompous enough to think that even after reading a few articles or books that I can reliably tell structural damage from easily repairable shoddy work. At least not enough that on a million dollar home purchase, I could risk being out of a home for a while or a couple of hundred thousand dollars.

But there are some buyers for whom this is not an impediment: ones who have enough capital that a bad house or two wouldn't make a big dent in their bottom line, and ones who don't truly understand the kind of risk they're taking and think they have a decent deal on their hands.

The result is that waiving inspections to buy homes is the new standard to be able to compete as a buyer at all, meaning there is now incentive to not fix serious issues in homes or even patch over them to make them less visible. Financial incentive for selling a better product reduces because the bad ones will sell. Quality of homes on the market goes down. Meanwhile those who can compete to buy the better deals are now a smaller population, but they still need homes. Price efficiency goes down because on average people are buying worse homes for more money.

That gatekeeping protects desperate people from being scammed into spending tons of money on ineffective, and possibly dangerous treatments.

Is it perfect? No. Could it be improved? Yes. But the rules exist for a reason.

You would still have FDA and the approval process, and it could continue to be strict (or even stricter). If vendors are lying about their product being FDA approved, that would be illegal (just like it is now). I don't see how this would change anything in that regard.

I'm surprised how many people are either forget or intentionally misrepresent the actual real-world scenario of letting people handle medical advice by themselves.

We already did this experiment 1-Javascript-Framework-lifecycle-equivalent ago.

https://en.wikipedia.org/wiki/Ivermectin_during_the_COVID-19...

Your imagined situation relies on the supposition that the new treatment is "promising" - how often do you think this is the case?

A person facing death from disease is desperate, and desperate people are easily taken advantage of. This is part of the reason the FDA exists - to protect desperate people from being ripped off.

The FDA can and should prevent unproven medicines that are not ready for human trials from being used without due diligence.

The links from OP are paywalled but the first few visible lines are enough to cast significant doubt for me on whether the treatment is even "promising":

> [Sarepta's] gene therapy for Duchenne muscular dystrophy failed to improve muscle function compared to a placebo in a large clinical trial

https://www.statnews.com/2023/10/30/sareptas-duchenne-gene-t...

> the drug failed a large, Phase 3 trial last year ... three review teams ... wrote that the data Sarepta submitted "cast significant uncertainty regarding the benefits of the treatment".

https://www.statnews.com/2024/06/20/sarepta-duchenne-elevidy...

I'm not sure what makes this treatment "promising" other than the gushings of the CEO. Are you arguing that we should give new treatments a free pass on regulations as long as its for a death-sentence disease and the CEO has connections?

There's already Expanded Access / Compassionate Care options for terminal patients. It doesn't require the FDA rushing through unproven medications.

No, not "promising but unproven" at all. This drug failed its clinical trial. It got its chance, and the evidence indicates it doesn't work.

This objection is pure ignorance. "Compassionate use" is already one of the expanded access exceptions, and has been for over 50 years.

Is it illegal to prescribe the molecule off label?

This is a good point. Doctors can prescribe drugs approved for disease X off label to treat disease Y even when effectiveness against Y has not been proven. In this case, the drug has not been approved for any disease so it can't be prescribed. Just goes to show how arbitrary the rules are.

I'm not sure that makes it "arbitrary." Approval is not just about effectiveness but also risks and side effects.

If we've gotten to Phase III, the risks and side effects are understood as well as they would be for a doctor prescribing off label. While I might not call it arbitrary, I would say it's an unappreciated edge case.

I’d like to see a payment structure more like a bounty for efficacy. If you think you can cure DMD, you know up-front what you’ll get paid, and it depends on how well it works, dosing schedule, side effects, etc. If your drug is safe but barely works, you get paid a tiny bit of money. If DMD patients’ families want the drug and the manufacturer is willing to sell it at the appropriately low price, fine.

IMO the actual failure here is the fact that Sarepta can charge $3.2M for a product without demonstrated efficacy.

A customer base of people with profoundly serious troubles at the edge of desperation who are looking for any glimmer of hope. An industry who's incentivized to charge astronomical amounts to an untapped market to recoup costs. A drug that seems to have failed based on multiple trials and 3 separate expert review teams. Now remove the approval requirements. What could possibly go wrong?

It's easy to yell paternalism but this doesn't look like a case of paper pushers getting in the way of a promising drug to me. Also, history is littered with examples of why "buyer beware" does NOT work, and a vast literature on information asymmetry, adverse selection, "The Market for Lemons", etc etc. Also, the FDA already has mechanisms to speed up new drugs getting to patients when the benefit is clear early on, AFAIK.

> Now you get to choose whether to take it or not.

The question is who is paying for these treatments? Drug companies are not shy about charging tens of thousands of dollars a year for a course of treatment that may or may not help. Insurance companies and Medicare partD will probably be reluctant to reimburse. Drug companies have large incentives to get patients to pay out of pocket, and no, they won't refund if the product is not effective.

Perhaps if the FDA were to create a new class of approval that states: Drugs under this class are shown to not cause harm but are also not proven to be helpful. They may be taken, but drug companies may not charge for supplies until efficacy is shown in controlled conditions.

The primary issue here is there are plenty of Snake Oil salesmen ready to tell you anything you want to hear and have no qualms about taking "somebody's" money.

I am sure creating a new class such as this, will also create a host of unintended consequences though.

By awarding approval to an ineffective drug, the FDA reduces competition that could otherwise have led to an effective therapy in the future.

Often it pays simply to remember what a rigidly ideological culture we inhabit.

Imagine it's 1986 and this story comes from SoViEt RuSsIa. Derek Lowe (who I hold to be adjacent to a National Treasure) would not be obliged to speculate about motives.

The entire bloviosphere would unanimously collapse into mockery.

The word is "corrupt." It's simple.

Well, it’s a good start anyway.

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