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Comment by drewg123 | Hacker News Reader

It seems like the key to making medical progress is realizing that not all treatments are "one size fits all" and figuring out why treatments that are safe and effective for some people are unsafe for others.

The vaccine from this story seemed to be safe and effective for some participants, but nearly killed another. How can we differentiate the people that it will help from the people that it could kill? This is a real problem in FDA approved medications. Just look at the side effects list for some of the "biologic" TNF blocking treatments for autoimmune diseases. Yet they are beneficial for most people.

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Human bodies are vastly different and one of the biggest difficulties is finding compounds that work the same 99% of the time, with minimal but known and treatable side effects.

There's a reason this research takes so long. Things might have gotten to market sooner decades ago, but it all comes down to a trade-off with potential good vs safety. When political maneuvering gets in the way, you can get things like the Vioxx disaster. Even with Vioxx, FDA monitoring and procedures did do what they were suppose to in identifying the problem and pulling it off the market.

The biggest problem really seems to be money, resources and funding the research. You might discover something promising, but your company will need to pay all those people, buy equipment and purchase animals to go forward. If you get to monkeys and lose a single one, you gotta go back to the beginning. You might find a side effect in 5% that's really bad/serious and your entire compound might need to be scrapped.

Companies need to make money off of those investments so the compounds that do succeeded might become insanely expensive. The entire process is pretty backwards and I know people who are biochemists in this field who get paid really shitty despite their important work. A lot of money goes to equipment, but a lot also goes to management and cronies in the shops that can fund this stuff.

It's a mess. There needs to be a better, not-for-profit model where a failed compound doesn't matter as much.

Right now, investing in drug development is just a bad use of resources. There's a huge amount of variation in clinical practice using the drugs we already have. A lot of that practice is undoubtedly sub-optimal or actively harmful, but we just aren't funding research into how we use old, boring, generic drugs.

If you go into cardiac arrest, you may or may not be given epinephrine. Some hospitals use it in their resus protocols, some don't. Nobody knows whether it works, but it's the subject of heated debate at anesthesiology conferences. Some trials suggest that it's marginally effective, others suggest that it reduces long-term survival rates. There's conflicting evidence on timing and dose. As you teeter on the threshold between life or death, someone might be giving you a drug based on decades-old studies performed on dogs, some clinical guesswork and a bunch of inconclusive research.

For the price of one drug that offers a few extra months of life to a handful of patients with a rare form of cancer, we could resolve several of these clinical debates.

http://anesthesiology.pubs.asahq.org/article.aspx?articleid=...

There needs to be a better, not-for-profit model where a failed compound doesn't matter as much

Phase II/III clinical testing is expensive, and the failure rate (i.e. low efficacy, compound simply doesn't perform as expected, and certainly no better than what's already at market) is high. That's what it is, there isn't much that can be done at that front.

Thankfully a few months ago Goldman Sachs directly addressed the elephant in the room: pharma yields bad returns, investment in pharma is inadvisable. There needs to be a different financing model, perhaps from the public purse.

In summery financing from the public purse with positive valuable results belonging to private parties that people like Sachs can acquire and jack up the price. What a fantastic idea.

There needs to be a different financing model, perhaps from the public purse.

How does that solve the issue at hand? As you said, development is expensive and has a high failure rate. Why would public funding change either one of those?

New antibiotics are high on the list of things that are needed, but they will only be used as treatment of last resort, this is where the traditional investment model fails. Development is too expensive to ever recover the outlays.

Right now science can't do anything about the high failure rates in Phase II and Phase III trials. The problem isn't to come up with a compound against your target of choice, it's that apart from clinical trials we don't have a way to predict if in real life it will perform better than placebo (Phase II) or adequately (Phase III).

While commonly used as an example, I'll note this isn't actually even always true for antibiotics.

The development of Fidaxomicin/Difficid is actually an example of a fairly inexpensive clinical trial (by clinical trial standards), and Merck didn't buy Cubist for $9.5 billion for a drug they don't think will recover their outlay.

At the very least it would spread the cost out over everyone rather than just the people who end up needing the drugs that pass the expensive process.

The cost is already spread over everyone. Drug companies are paid by insurance companies and the gov't (public healthcare). Those entities are paid through insurance premiums and taxes.

>Companies need to make money off of those investments so the compounds that do succeeded might become insanely expensive. The entire process is pretty backwards and I know people who are biochemists in this field who get paid really shitty despite their important work. A lot of money goes to equipment, but a lot also goes to management and cronies in the shops that can fund this stuff.

science staff being underpaid relative to the value they provide is the norm. everyone knows the scientists are there for the love of it.

the equipment is pricey, sure. million dollar machines, yada yada yada.

but the marketing budget is far higher than the r&d budget. it isn't even close.

and yeah, it's a mess. from my experience on the inside, companies are willfully deceptive at all phases of the research and clinical trial process. failures are swept under the rug as much as humanly possible. especially if those failures endanger a real person.

if a person gets hurt in a trial, i guarantee you that there was knowledge of the risk that was drastically downplayed.

drug companies test tens of thousands of candidate drugs before moving to trials. in the last round of testing before trying to move to clinical trials, the drugs are typically very similar variants of each other. problems are found in most. the one candidate where problems aren't found, likely by luck, is the one that advances. survivorship bias is intentionally played up as evidence of validity. then, of course, the "black swan" negative event happens. stock price plummets.

cue statements regarding how much they care about trial patients, and the problem couldnt have been foreseen, etc etc.

but they knew all along that it would happen. it was happening to mice with the drug's sibling candidates which didn't make it to the clinic.

Precision medicine offers some hope here. With cheaper genetic sequencing it's becoming practical to correlate effects and side effects with particular genotypes of the patient or infectious agent. Still though you need a lot of test subjects to isolate the differences.

> There's a reason this research takes so long. Things might have gotten to market sooner decades ago, but it all comes down to a trade-off with potential good vs safety.

Agreed. We’re way past the sane point on the trade off. Aspirin would not pass FDA review under the current regime. Efficacy testing doesn’t appear to do much good but it clearly makes getting a drug to market slower and more costly.

For more on this see http://www.fdareview.org/

Efficacy testing doesn’t appear to do much good

Come again, it's not important that any medication performs as advertised?! The purpose of Phase II testing is to determine if the new compound is better than placebo; the success rate is ~ 30 %, 70 % are no better than placebo. 70 % of candidates are as good as taking nothing at all.

In a public health system this is the most important question to be answered: does the new treatment offer a greater benefit to patients - if not you can't ask the public purse to pay for it.

I can also see the risk of backlash - the public perception of bigpharma is already low; if it begins to offer expensive treatments of low value trust in the institutions will erode further.

> aspirin wouldn’t pass

We have a number of drugs in the same class that are as or more effective with less frequent adverse effects, and the same price to market. It is also one of the leading causes of toxic ODs presenting to the ED. Aspirin shouldn’t pass as an over the counter Anywhere, and wouldn’t but for historical inertia. Don’t confuse familiarity with safety.

> efficacy testing doesn’t appear to do much good

Efficacy testing is literally how we determine whether a drug works, and what the magnitude of its effects are. Without it, we’d have no idea if a drug worked, if it worked better or worse than competitor drugs, if it worked better or worse for some conditions or sub populations, etc. It’s -the- key information generating step on drugs. This comment is ridiculous to the point of caricature.

>fdareview

A site from the far-right, unknown-anywhere-but-Fox-news Independent Institute. Can you guess before popping the link open whether they advocate on lightening regulatory burdens on pharma companies?

>> aspirin wouldn’t pass

>We have a number of drugs in the same class that are as or more effective with less frequent adverse effects, and the same price to market. It is also one of the leading causes of toxic ODs presenting to the ED. Aspirin shouldn’t pass as an over the counter Anywhere, and wouldn’t but for historical inertia. Don’t confuse familiarity with safety.

Could you add some more data to back up your statements? For example, you state "It is also one of the leading causes of toxic ODs presenting to the ED"

>...During the latter part of the 20th century, the number of poisonings from salicylates declined, mainly because of the increased popularity of other over-the-counter analgesics such as paracetamol (acetaminophen). Fifty-two deaths involving single-ingredient aspirin were reported in the United States in 2000; however, in all but three of these cases, the reason for the ingestion of lethal doses was intentional—predominantly suicidal.

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

Considering that literally thousands of tons of aspirin are consumed every year, this safety record likely compares well with other drugs.

As a comparison, the most commonly used alternative to aspirin is acetaminophen and that is certainly much more dangerous:

>...Many over-the-counter and prescription-only medications contain paracetamol. Because of its wide availability paired with comparably high toxicity, (compared to ibuprofen and aspirin) there is a much higher potential for overdose.[88] Paracetamol toxicity is one of the most common causes of poisoning worldwide.[22] In the United States, the United Kingdom, Australia, and New Zealand, paracetamol is the most common cause of drug overdoses.[17][89][90] Additionally, in both the United States and the United Kingdom it is the most common cause of acute liver failure.[91][7]

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

>...A site from the far-right, unknown-anywhere-but-Fox-news

I agree with you that efficacy testing of potential new drugs is important, but adding a statement with pejorative labelling like this feels somewhat like you are simply trying to poison the well.

>Data

The most recent public data from the american association of poison control centers is 2016. For toxicity events alone they don't break out analgesics into sub-groups, but for fatalities acetaminophen is in fifth place with 5.39% (there's also acetominophen combinations but those really don't count - they're all opioid combinations, and really represent an entirely different phenomenon). Aspirin is in 16th place, with 1.91% of fatalities. For scale, opioids are 8.3%, and anticonvulsants are 1.76%. Most of these are multi-substance exposures. For instances where there was only a single substance exposure, acetaminophen was about 12% and aspirin 3% (opioids 6.4%, anticonvulsants 0.51%). Ibuprofen, with 81k case mentions (vs. acetominophen's 58k and aspirin's 17k), didn't make the top-25 killer list.

I didn't dig up the AAPC article mentioned in wikipedia, as it's about two decades old now, but the AAPC annual report I'm looking at right now shows most (~13k/17.5k) sole aspirin exposures were in the <12 crowd. It's not a big demographic for suicide.

As to my statement that we have better drugs, the Oxford Pain Group has released the Oxford League Table for relative comparisons between NSAIDs, based on a meta-analysis of comparative trials. With a standardized measure of "50% of pain relief over 4-6 hours" as a successful treatment, the league table ranks NSAIDs by the number of patients you need to treat to achieve said outcome for one patient. Aspirin 1200s (.3 of your max recommended daily dose) are in 16th place, with an NNT of 2.4. Acetaminophen 1000s (1/4 of your daily max dose) are in 34th place with 3.8. Ibuprofen 800 (1/4 of your daily max dose), drug of choice for every doc I know, are in second place with an NNT of 1.6.

>Paracetomol wikipedia tox

I didn't say aspirin was the single biggest killer. I said we had other drugs "as or more effective with less frequent adverse effects, and the same price to market," and that "it was one of the leading causes," not the single biggest cause. I don't think the wikipedia page really contradicts that?

> but adding a statement with pejorative labelling like this feels somewhat like you are simply trying to poison the well.

I disagree. If someone links to a peer-reviewed article in a respected journal and the response is "that author is a shill," you're coming down on the side of ad hominem. But when someone links to an NRA website and says "you should read more here about gun safety here," ... it's entirely appropriate to point out the source of that information. Lobbyists, propagandist "think tanks," and other highly partisan groups that build a business model on trotting out talking points for their respective parties absolutely deserve being identified on sight as such.

>...Aspirin is in 16th place, with 1.91% of fatalities. For scale, opioids are 8.3%, and anticonvulsants are 1.76%. Most of these are multi-substance exposures. For instances where there was only a single substance exposure, acetaminophen was about 12% and aspirin 3% (opioids 6.4%, anticonvulsants 0.51%). Ibuprofen, with 81k case mentions (vs. acetominophen's 58k and aspirin's 17k), didn't make the top-25 killer list.

One obvious issue is that this data isn't the complete picture - obviously the amount of consumption of the drug is the other half of the picture. I've seen estimates that over 100 billion aspirin doses are consumed each year of aspirin - I doubt that much is consumed of other drugs you listed. If aspirin was no longer available over the counter, wouldn't that just increase the risk of overdose for its competitors? (Particularly for acetaminophen).

In terms of safety,. the FDA has also singled out Ibuprofen and other non aspirin NSAID drugs for: health risks that (they claim) aspirin doesn't have:

>...People who take nonsteroidal anti-inflammatory drugs (NSAIDs) (other than aspirin) such as ibuprofen may have a higher risk of having a heart attack or a stroke than people who do not take these medications. These events may happen without warning and may cause death.

https://medlineplus.gov/druginfo/meds/a682159.html

Any of these deaths caused by other NSAIDs would likely not be attributed to Ibuprofen on the death certificate.

In terms of efficacy, you wrote:

>...Ibuprofen 800 (1/4 of your daily max dose),

3200 mg is the daily max dose when under the care of a Doctor. The instructions on the OTC bottle will say to use 1200 mg per day. So as an OTC drug (which is what we are talking about here) that is more like 2/3 of the suggested daily dose.

>…I didn't say aspirin was the single biggest killer. I said we had other drugs "as or more effective with less frequent adverse effects, and the same price to market," and that "it was one of the leading causes," not the single biggest cause. I don't think the wikipedia page really contradicts that?

What you originally wrote was:

>…Aspirin shouldn’t pass as an over the counter Anywhere, and wouldn’t but for historical inertia.

Aspirin is likely available over the counter in just about every country in the world. Considering the massive usage of this drug, the adverse incidents seem low. The number of deaths from overdose are minuscule compared to the usage and I think you agree it is safer than other OTC counter drugs such as acetaminophen. In terms of efficacy as an OTC drug it seems comparable to the competitors.

>...But when someone links to an NRA website and says "you should read more here about gun safety here," ... it's entirely appropriate to point out the source of that information.

You weren't just pointing "out the source of the information" - the group behind the info is on first page, that wasn't a secret.. What you wrote was:

>…A site from the far-right, unknown-anywhere-but-Fox-news Independent Institute.

Terms like "far-left" and "far-right" are often casually used as a pejorative against a person or group. Neither of these terms is well defined, but most people consider "far-right" to be related to Nazis, skinheads, etc. - i.e. (possibly dangerous) kooks who should be ignored. Looking at the wikipedia entry for the Independent Institute:

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

I don't see any evidence that they are a hate group. You also wrote

>…unknown-anywhere-but-Fox-news

Are they often quoted as a source on Fox news or a guest on a Fox show? From the wikipedia page it sounds like they would be in disagreement with Fox news on various issues like the Iraq War.

Intentional or not, trying to shut down discussion by labelling someone you disagree with like that is poisoning the well. Far too many members of the public just stay in their ideological bubble and ignore any arguments except those they agree with. It is easy for the average person to be skeptical of ideas they disagree with, it is much harder for them to be skeptical of ideas they want to believe. There is nothing wrong with pointing out disagreements with an argument someone makes (as you did earlier) or pointing out possible conflicts of interest that weren't disclosed by the authors, but labelling someone you disagree with as a kook that should be ignored on principle isn't really the same thing.

> It seems like the key to making medical progress is realizing that not all treatments are "one size fits all"

The medical community has realized this, and been tackling this problem for a few millennia. Hippocrates addressed the topic.

>and figuring out why treatments that are safe and effective for some people are unsafe for others.

That’s the hard part. It’s why we pay attention to how we construct patient recruitment, sample demographics, assess the metabolic pathways by which a drug is processed and study genetic variants in those pathways, develop biologics with different types of chimeric proteins, retrospectively analyze adverse events for patterns, etc.

Each and every one of those things that are standard elements of modern medicine and rational drug design are about understanding variability in drug response. We haven’t perfected this yet - nor are we close. Anyone who wishes to lend a brain cell is welcome.

>"we pay attention to how we construct patient recruitment, sample demographics, ... etc"

I was told the opposite the other day:

"the fact that clinical trials seek people maximally healthy but for the target conditions rather than a representative sample of those with the target condition is a very frequent complaint." https://news.ycombinator.com/item?id=16868660

>"Anyone who wishes to lend a brain cell is welcome."

Its pretty misleading to promise this. People who disagree with the "publish an endless series of statistically significant differences" paradigm are not going to find it at all welcoming.

> "the fact that clinical trials seek people maximally healthy but for the target conditions rather than a representative sample of those with the target condition is a very frequent complaint."

Those aren't quite in contradiction. So, where you start, is with a trial that tries to eliminate meaningful comorbid conditions to allow it to answer the question: "Does this drug work for Disease X?", rather than the question "Does this drug work for Disease X when accompanied by Diseases Y and Z?" There are just far, far too many permutations of X, Y, Z, etc. to allow them all into a study and even pretend to have answered the question about the drug. So, it's not where you start. But, you're absolutely paying attention to patient demographics here, that's part of the point: can we come up with a reasonably homogenous patient pool for step 1? That's not really about being "optimally healthy," it's about homogeneity, except where the latter implies "not a giant variety of comorbid diseases."

But, as I hope I've made clear in the way I reiterated it, that's the initial step. Because, hey, we really do need to answer the question about Drug A for Disease X before we start working on the various permutations of Disease X with other diseases. The latter is usually studied through retrospective analysis rather than RCT. Why?

A given study has only a certain sample size to work with. There's this sort of odd implicit idea that small sample size is merely an issue of study design, but not really: in practice, a research group only has a catchment area of a certain size - they'll only be able to catch so many patients per unit time, and you can't run a study forever (both because you run out of grant funding and because the state of the disease and therapy moves on.) The more specific you get - e.g., people with Disease X and Y and Z, but neither Y and Z to be more than moderately severe - the fewer patients you can potentially recruit, to the point where the final result is statistically meaningless. This isn't really the worst thing ever: the less capable you are of recruiting patients because of their rarity, the less useful such a study would be to the public because of their rarity. As a practical effect, you can't really build a study to control for every meaningful confounding comorbidity. So, we tend to wait for data to accrue and analyse it retrospectively. It's not as good as an RCT, but it's the best we can do under practical constraints.

It's one of those things worth criticizing, in theory, but continues because we don't have the means to do better. Ideally we'd have studies of 20k+ people selecting for significant sub-groups of each permutation of common comorbid conditions. That's just beyond any hope of organizing, running, or paying for.

>>"Anyone who wishes to lend a brain cell is welcome."

>Its pretty misleading to promise this. People who disagree >with the "publish an endless series of statistically >significant differences" paradigm are not going to find it >at all welcoming.

That's simply untrue. I know people working in operations research who are developing novel predictive models for ED patients to predict where they'll need to be sent after workup (and how to prep the appropriate hospital dept. for their arrival, and to estimate when that will be); the VA does shit-tons of operations research. I know people working in the basic sciences who are working on developing ever-more-sophisticated models of the current state of physiology/biochemistry, to allow for increased accuracy of predicting a drug's effectiveness and toxicities before moving on to in vitro testing. And an interesting negative result is about as easily published these days as an interesting positive result (even Easterbrook's big '91 paper on publication bias found that it was for observational and lab studies, but couldn't identify bias in RCT publication.)

The full variety of interesting work to be done in clinical trial design isn't super obvious from the outside. Especially since the folks moaning and whining about it tend to be academics, and a big chunk of good clinical trial work doesn't involve many university academics, and the other cool work (e.g., operations research) is being done in industry and at the VA. But "not super visible to university academics, who are the ones talking about publish or perish" and "non-existent" are very different things.

There's a lot being claimed here that seems to go directly against my experience, I'll focus on what is easily verifiable:

>"(even Easterbrook's big '91 paper on publication bias found that it was for observational and lab studies, but couldn't identify bias in RCT publication.)"

I'm not familiar with the Easterbook 1991 paper but that is a pretty strange thing to claim since it is even one of those criticisms that academia has managed to turn into it's own area of study. It didn't look closely at any of these papers but just for example:

>"we review and summarise the evidence from cohort studies that have assessed study publication bias or outcome reporting bias in randomised controlled trials. [...] Direct empirical evidence for the existence of study publication bias and outcome reporting bias is shown. There is strong evidence of an association between significant results and publication; studies that report positive or significant results are more likely to be published and outcomes that are statistically significant have higher odds of being fully reported. " https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702538/

>"We conclude that RCTs investigating antipsychotic drugs suffer from substantial outcome reporting bias" https://www.nature.com/articles/tp2017203

In the case of vaccines specifically, there is just a surprising amount of things we still don't understand.

Vaccination is positively ancient technology (Smallpox circa 1796), but it is still difficult to say why e.g., some vaccines are broadly effective at producing immunity and some aren't (and what the factors at play are in the recipients), or why we can produce successful vaccines to some diseases and not others.

A specific example: the efficacy of BCG vaccination (tuberculosis) varies by manufacturer and the reasons for why that is are still unclear.

There are a number of large NIH-funded initiatives that aim at understanding the complex cellular and molecular interactions that result in immunity as a result of vaccination under the Human Immunology Project Consortium (a bunch of high profile papers in Cell, etc. over the past few years).

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