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FDA Approving Drugs at Breakneck Speed, Raising Alarm (msn.com)
106 points by eplanit 48 days ago | hide | past | web | favorite | 77 comments

This is a good thing. People die, and die sooner, when the FDA cannot adapt its approval process to drugs and tools for patients who sadly have little downside to trying them.

In my own little corner (diabetes) it’s been nice to get monitoring tools earlier than they once would have been approved, and for my medical team to confidently plan for equipment changes based on future approvals.

Only a fraction of drugs treat life threatening condition in some new way. Painkillers for example represent a surprising fraction of all drugs and generally have a close equivalent. https://www.drugs.com/condition/pain.html

Taking enough time to endure a new acne medication or Viagra alternative etc is reasonably safe is very much worth spending some extra time.

Edit: This does seem to be focused on needed medications without close equivalents but that’s a fairly arbitrary line.

Close equivalent can still be something you can't take. For example, if you're one of the unfortunate people with no activity on your CYP2D6 enzyme, there are essentially 4 pain medications that you can take at appropriate doses once you need something stronger than advil: Morphine, Dilaudid, Oxymorphone and Fentanyl, and there are reasons why doctors prefer other narcotics before prescribing any of those 4. Other pain medications will work, but you'll likely need inappropriately higher doses[0], which can lead to other problems (like overdosing). Likewise if you process faster than a normal person (i.e. you have more activity on that enzyme) you can overdose at normal prescribing doses. Close equivalents for some people can indeed be the difference between life and death, even if the condition itself isn't life threatening.

[0]: https://www.ncbi.nlm.nih.gov/books/NBK100662/

That’s a very good point, but then we are talking about edge cases and a delay measured in weeks to months. So, the benefit from catching 1 bad drug could outweigh the benefits from releasing 100 drugs slightly earlier.

It’s not an easy choice, especially when the risks are often hypothetical and the benefits so clear.

It’s interesting looking at lists like this and considering where things broken down. https://en.m.wikipedia.org/wiki/List_of_withdrawn_drugs

The FDA already takes that into account when doing a risk/benefit assessment.

If you're looking to treat relatively health people for most of their lives (say a drug that precent type I diabetes), the FDA will scrutinize the hell out of it.

If you're looking to treat someone who is dying (e.g. metastatic cancer), then the FDA is much more lenient in their analysis.

It is as long as the FDA can operate flexibly enough to not spend extra time where they shouldn’t. If they can’t, as seems to have been the case historically, then it’s best overall from a mortality and longevity perspective if they err on the side of faster releases. Note that faster operation also means they can more quickly act on feedback from the market and medical practitioners post release.

The problem is the approval of drugs that don’t actually work, and so are actually harmful.

the approval then means that companies can target people who are desperate with extremely expensive snake oil. The victims of this have no recourse if/when the drug has caused problems.

There is obviously a tradeoff between risk and speed. The article provides evidence that speed is increasing. I don't think the article provides any compelling argument that approvals are too fast. Do you?

I thought the FDA summed it it up well in the article:

>“We would expect every once in a while that we would be wrong,” with an accelerated approval, she said. “Otherwise, we aren’t taking any chances, we are still making them wait too long to get their hands on this therapy that will extend their lives.”

> There is obviously a tradeoff between risk and speed. The article provides evidence that speed is increasing. I don't think the article provides any compelling argument that approvals are too fast. Do you?

Vinay Prasad is a cancer expert and an outspoken critic of too fast approvals of drugs. He has done research on it, I could e.g. find this:


Is the FDA Too Conservative or Too Aggressive?: A Bayesian Decision Analysis of Clinical Trial Design

The results for conventional fixed-sample randomized clinical-trial designs suggest that for terminal illnesses with no existing therapies such as pancreatic cancer, the standard threshold of 2.5% is substantially more conservative than the BDA-optimal threshold of 27.9%. However, for relatively less deadly conditions such as prostate cancer, 2.5% is more risk-tolerant or aggressive than the BDA-optimal threshold of 1.2%. We compute BDA-optimal sizes for 25 of the most lethal diseases and show how a BDA-informed approval process can incorporate all stakeholders’ views in a systematic, transparent, internally consistent, and repeatable manner.


Im not familiar with his work, but from what you posted, it seems Prasad takes issue with the use of surrogate end points in trials, not fast track approvals. I tend to agree that surrogates and bio markers are a huge problem, but think they are a necessary evil. Drug development would screech to a halt if developers had to wait another 4-5 years for survival data. What we need is more Pase 4 postmarket trials with direct endpoints.

Interestingly, the paper linked shows that in some respects, fast tracked drugs have a better track reccord. This shouldnt be surprising as the best drugs are fast tracked.

>18 drugs failed to improve overall survival (in 6 of 15 accelerated approvals and in 12 of 21 traditional approvals)

You’re mixing two things:

Doesn’t work = efficacy trials

Is harmful = safety trials

iirc the safety trials come first. A lot of drugs get stalled in efficacy trials because they might only work for some patients and the sample set is small or poorly chosen.

I see no reason to stall drugs that are proven safe, even if they might not be effective for all patients, as long as there is full disclosure and informed consent. Freedom to choose is a good thing.

FDA approves drugs following Phase III

Phase I determines safety. Phase II determines efficacy. Phase III is larger scale, randomized, and blind to give the FDA more information on the range of potential adverse effects and the effectiveness of the drug. FDA is supposed to care about both. The acceptable safety of a drug is relative to the effectiveness of it (i.e. a drug may be more dangerous or have more adverse effects, but it’s deemed “worth it” due to the effectiveness of the drug while of course maintaining a minimum safety risk for all drugs). In other words, both safety and effectiveness are both supposed to be taken as equal halves of the whole by the FDA.

But you also want to consider alternatives. If you have something which is only effective for a small percentage of people even though it's really dangerous, that may still be worth it as something to use for people for which existing treatments were ineffective and the remaining alternative is certain death. Saving 15% of those people can be better than none.

> I see no reason to stall drugs that are proven safe, even if they might not be effective for all patients, as long as there is full disclosure and informed consent. Freedom to choose is a good thing.

I do.

For every treatment you are taking, you could have been taking some other treatment that might be more effective.

If we have no idea whether or not a drug is more effective than placebo, we should not be administering it.

This perspective is very frustrating to me. Why in the world would a sane person take a drug with unproven efficacy when others with proven efficacy are available?

However, there are many cases where there is no alternative drug or treatment that has been tested for efficacy, and so you’re stuck with hospice as standard of care.

It’s one thing for a doctor to recommend administration of a medication, it’s another thing entirely to make it unavailable for those that are in a position to make the choice for themselves.

> This perspective is very frustrating to me. Why in the world would a sane person take a drug with unproven efficacy when others with proven efficacy are available?

Because they don't want the side effects of proven treatments, and they hope that snake oil will help them.

If people were rational about their health, homeopathic supplements, and other similar bullshit wouldn't be a billion dollar industry.

If you can't prove that your treatment works, you shouldn't be advertising it as a medical treatment. Advertise it as a non-medical non-treatment.

"You’re mixing two things:"

Being ineffective can be very dangerous as a person taking a drug expecting it to alleviate their condition finds no relief and thus dies from their condition.

You did not fully read and comprehend the parent post.

Post implied fairly plainly that “doesn’t work == harmful”, is there another way to read that?

While I agree with you... if you take the side of the Medical and Insurance industry, it works great. Money is extracted before they died with a high margin process. The incentive is perverse, but it's real and effective.

We need to allow people to self care so you can hack your own diabetes.

I wish I could buy my own life sustaining hormone that I've been using for 20 years and understand better than most doctors outside endocrinology.

I completely agree. It’s shameful that the existing open source DIY projects have to be careful about how useful they allow themselves to become. Thankfully, some of their principles have been picked up by the industry, but it’s taken too long.

A lot of harm is done to diabetics by denying them better treatments and tools in the name of avoiding extreme highs and lows.


In the self-care continuum, where would you place yourself or how do you define it? I hope such insight may help in the constructive exchange of ideas valued in this forum.

Your comment was dead from flags. I believe it’s against the guidelines to complain about downvotes, and it also invites pile-ons.

I have a friend who has to regularly go to Europe to replace her implantable pump. It's not approved in America because the bureaucrats haven't gotten around to it. So long as there's no false advertising, let people try treatments that work for them, even if there's risk. Said friend has enough money that she's okay, but most others aren't so lucky.

I dated someone with an external pump. It came off one day and caused so many problems. Just slid from sitting on the couch to the floor watching tv and the cushion caught the pump and broke it off.

I immediately thought that type of failure should be recoverable without a hospital visit and surgery and tried to figure out why it wasn't.

My mind immediately set to making it so and was held back by the fear I could go to prison for practicing medicine without a license.

"I love you. I wish I could fix you. I could fix you."

"I know you could. I wish you could."

There are some other options. I use a pump (OmniPod) that is entirely attached to my body. There's a small plastic pod that's taped to the skin and operated wirelessly.

My chief complaint is that the FDA is overly restrictive. They force manufacturers to make the products expire earlier to head off concerns about them working less efficiently near the end of the cycle. Diabetes is a disease who's treatment is entirely about guesstimating but the FDA does not take that into account when approving devices.

[T1D who used an external Medtronic pump for years here]

Normally that kind of failure would be quickly recoverable without a hospital visit/surgery, I’m sorry that this one was not.

So, who is at fault when you die or who pays when you wind up in the hospital?

This isn't theoretical--someone already wound up in the hospital "hacking their diabetes". And the FDA came down on the companies involved in manufacturing the devices--even though they had NO involvement.

I'm sympathetic and recognize that modern technology could be doing MUCH more for diabetic patients. However, my measure of importance is how much money is being thrown at the problem. And there simply doesn't appear to be very much money being tossed around for a medical system that will have to go through FDA approval.

If you kill yourself when doing medical experiments on yourself, you are at fault.

This should be obvious.

Now the question is, when you kill your children or family because you're doing medical experiments to try to cure them, who's at fault?

Because there are people and groups drinking bleach and treating it as a cure-all for diseases. I don't think going back to the old American Wild West of snake oil selling for diseases is a good idea.

Who is at fault when you drink yourself into a coma or fall out of a tree or smoke yourself into cancer?

It's ok to do those things but not try to care for yourself?

> “It isn’t that we changed our policies and are saying we are going to approve drugs faster,” said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, who joined the agency under President Ronald Reagan. “The difference now is we are going to see more of those because of the science. If there are people out there with no options and they have terrible diseases, we are going to get those drugs to them as fast as feasible.”

> But even as drugmakers, investors and patients cheer on the agency’s pace, patient-safety advocates argue that speed comes at a price. Studies show medicines approved on a faster time line are more likely to have safety problems emerge after they become broadly available, while other treatments offer fewer benefits than anticipated.

Not sure I understand the concern:

- "studies show medicines approved on a faster time line ...": which study(ies)? And that was the case for previous track records, which says nothing if the FDA is making the same mistakes that they may have done 20 years ago.

- "more likely to have more safety concerns once they are broadly available while other treatments offer fewer benefits than anticipated", wait, do such studies actually have drugs that are virtually identical in all properties and where the only factor that changed is the approval timing? Because if that's not the case, you are just comparing drugs with different profiles, different indications, and different targets, which is pretty much apples and oranges. Good luck making conclusions based on that.

I am not aware of the FDA or any other regulatory body at this time starting to remove regulatory requirements to speed up approvals. The typical things we see nowadays is an exception for "orphan indications" where there is no good treatment available and people are dying without anything to try. It seems fair that they take in account patients' needs when it comes to expediting the last bureaucratic mile to ensure new drugs can save more patients. At the end of the day, patients are also free to refuse newer drugs (and doctors usually tell them when a drug has just been approved and when there is lack of much safety experience beyond clinical trials) so I don't see how you can frame this whole story in a negative light.

I think this is the key section:

_"It’s not just speed. The FDA also is approving more drugs, hitting a record 59 new therapies in 2018. Almost three-fourths received a priority review. That, combined with more efficient data collection, is responsible for the faster FDA action, said Aaron Kesselheim, a professor at Harvard Medical School. Companies are also communicating earlier and more often with the agency, which can head off issues at preliminary stages and help them get products through on the first attempt, he said."_

So as in any field, better communication with stakeholders improved the process and eliminated some issues earlier.

Then, better data collection helps them evaluate studies better. I bet it also reduces the back and forth and the "what does this mean" aspect of the studies after.

And then companies can pay for expedited evaluation.. which if they've been communicating clearly all along and have better data, doesn't seem far fetched.

The next thing you know, someone will suggest clear planning with stakeholders, code reviews, and unit tests will improve code quality and even ship dates! But that may be crazy talk.

Not to mention just because the pace has increased doesnt mean individual drugs are being released at "breakneck speed".

How about we raise an alarm when drugs aren’t approved promptly? People die when good drugs are held up in bureaucracy.

Woah that's quite a claim. Care to expand?

There are plenty of example of drugs costing 10-100x what they normally would, which pharma companies get all the heat for, are drugs that would otherwise have plenty of competition but dont due to to backlogs at the FDA.

Including the most famous one: Epipens


Doc here.

I was at a continuing education course last year. FDA approved a new narcotic very fast. A non narcotic alternative is taking forever to approve.

Its name is Maxigesic. Tylenol and ibuprofen in one pill.


As someone who works in the drug industry, when Maxigesic is approved, please don't prescribe it. Just tell your patients to take one each of the OTC drugs, they are dirt cheap (like $0.02 per pill).

The market is full of drugs that are combinations of OTC medications and usually they are way more expensive. Even if they didn't go nuts with the price, why make a patient pay $0.50 per pill when they could take 2 for $0.04?

Some patients have a lot of pills to take, and they would rather pay more to take fewer. Maybe they have trouble keeping track of them, maybe it is just pill fatigue. Maybe they have trouble swallowing for one reason or another. Combo pills could be a good thing for a subset of the population. Sure, it requires doctors to be on top of their game and patients to research what they are taking and ask questions, but that doesn't mean it isn't a good idea to have it available as an alternative.

As to the question about why it is taking so long at the FDA, I imagine it isn't a very high priority because there are alternatives.

I don’t disagree that pill burden can be an issue.

The problem is the lack of transparency into cost which results in some drug companies taking advantage.

Combine two pills that cost $0.10 each into one pill that costs $0.15? Reasonable.

Do the same and charge $5 per pill? Ridiculous. Problem is doctors and patients don’t know it costs $5 and insurers can’t be bothered to push back. Suddenly you’ve increased the cost of therapy by 50x.

That’s what I do now.

Good stuff. Lots of doctors don’t. Not out of bad will, but they just don’t have the time to dig into it.

That’s very strange. People have been alternating/mixing Tylenol and Ibuprofen for nearly 60 years. Don’t we know how they interact?

I don't know about this drug, but they may be using a different manufacturing process or something else that is undergoing scrutiny.

Yes we do. People see the equation as drug + drug = relief. Pharmaceutical companies see the equation as drug + drug + patent = $

What process is Maxigesic being approved under? I assume an aNDA, which is for generic drugs.

The FDA has a massive backlog for generic drugs, while novel drugs (NDA) don’t.

What do you think the reason is? I only ask because there are (probably) few Doctors here and it's an interesting question.

Yes.. fda approves combination pills seperate to each drug on it's own. While i'm not a pharmacologist, it dies seem odd

not a doctor, I for one will prefer a single pill instead of two pills , Swallowing pill is unpleasy for me, if there are too many pills , There is higher chance of mistakes (like forgetting, mixing doses etc) .I will pay a reasonable premium for one combination pill instead of two pills.

Clinical trials are complicated beasts. The simplest answer is likely that the CRO running the trials - at least I hope its a CRO - isn't set up to target the kind of patients/doctors needed for approval or they don't have funding immediately available to speed that process up at the necessary scale.

>Maxigesic. Tylenol and ibuprofen in one pill.

What's the point of this, compared to just having half a pill of tylenol and half a pill of ibuprofen?

If anyone reads this for medical advice (and I really hope they wouldn't be taking advice directly from HN without any filtering), you don't combine them in equal proportions.

Yes, you combine 500mg of acetaminophen and 150mg of ibuprofen. Ibuprofen only comes in 200mg pills, so if you want to be really spot on, take the liquid stuff for kids.

That seems pretty high for acetaminophen and low (proportionally) for ibuprofen. Why would you prescribe that?

I wouldn't. I take naproxen. That's just whats in the drug if you don't want to wait for the FDA to approve a pill that combines the two.

500mg is the max for ace a doctor is recommended to proscribe (on it's own). 150 is well below the max for ibu. Also I think you may have mixed up the grandparent commentator that stated they were a doctor and the parent that may be a doctor but hasn't made that claim here.

Am doctor. Routinely prescribe 1000 mg of Acetaminophen.

Thanks for pointing out that I'm wrong. I googled more and realized the numbers I cited were completely wrong.

500mg is normal for a single extra-strength pill of acetaminophen

200mg is normal for ibuprofen, and prescriptions for 800mg versions are not unusual.

Meanwhile 500mg is, I believe, more than they combine with opiates and acetaminophen does lead to death via organ failure on the order of hundreds of people a year. I was curious why they weighted the acetaminophen proportionally so much higher than the ibuprofen.

It still seems odd. Both Tylenol and ibuprofen are good to keep around with your basic home health care supplies. They are available in cheap generics without a prescription. They have different things they are best at, so stocking both is quite reasonable.

Unless they need to be prescribed in ratios that can't be achieved reasonably with the cheap OTC pill dose sizes, it's not clear to my why I'd want a combined bill instead of just taking separate pills.

Taking more than one pill is less convenient, but except for people who have trouble with pills in general I doubt they would want to pay more for that convenience.

Even in the case of fairly high doses, it is not too bad. A few months ago, for example, I somehow managed to get a painful rotator cuff injury while sleeping (no idea how), and my doctor told me to take 1000 mg Tylenol every 8 hours and 800 mg of ibuprofen every 8 hours. At the most common OTC strengths, that would be two Tylenol pills and 4 ibuprofen pills.

If we had decent competition in medicine this wouldn't be an issue. Either people would agree with you and not buy it, or some would buy it, and no one would be worse off.

For the record, I didn't pretend to give medical advice at all.

I realize in retrospect my comment might have appeared that way. I meant only that people might (possibly) read your comment and be misinformed. I meant it might be mistakenly read as legal advice, not that it was.

The point is that you have to pay 20x for the convenience of one pill.

*have the option to

It's a damn shame that doctors often fail to tell people about cheaper and more irritating alternatives, but there's nothing wrong with giving people the option to pay more for a better experience.

You often see this in terms of number of times a drug had to be taken per day. There'll be a generic that needs to be taken say three times a day, and a newer drug that only needs to be taken once.

I highly doubt every manufacturer of Ibuprofen or Acetaminophen would decide to throw in the towel if this new drug was released.

If I had to take a guess it’s because drug A + B != AB

The drugs in question could, combined have deleterious effects (say if their extortion mechanisms are the same).

This shouldn’t be a problem because Tylenol + Advil has been done for decades. However, a beauricracy doesn’t see it as a solved problem to fast track unless there is a specific fast track for this exact scenario.

Might have to do with the claims are they seeking for Maxigesic?

FDA is grossly understaffed. And more importantly, its policies are directly responsible for the skyrocketing prescription drug prices.

Could you give some examples? As far as I know, the policies of Congress are what is responsible for skyrocketing prescription drug prices.

Same thinking here. I don't believe the FDA is forcing drug prices onto the public; it seems to be a system enabled by congress and abused by the public sector.

What party has some sort of vested interested (presumably monetary) in slowing down FDA drug approval? Perhaps I'm being a bit pessimistic here, but after reading the article I don't really see any motivation for the "raising alarm" statement in the title, or even a reason anyone would bother publishing this in the first place.

I looked up the "consumer watchdog" that I'm guessing had something to do with this article, and their front page is just an "Impeach Trump" advertisement. See https://www.citizen.org/. Also, if you click their "About Us" page, a few lines down is: "We don’t participate in partisan political activities or endorse any candidates for elected office."


We've been hearing for years about accelerated drug candidate discovery through better tech and automation, and anecdotally a boom in clinical trials informatics etc, so not surprising

Enough gazillion dollars can compress time and expand space.

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