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Comment by danieltillett | Hacker News Reader

The problem developing new antibiotics is not the science it is economic and regulatory. Let's say you are crazy enough to pay the enormous cost of bring a new antibiotic through the regulatory process, your new antibiotic doesn't get used by doctors. They put the new antibiotic on the shelf to be used in emergencies when all the other antibiotics haven't worked. Your sales are then near zero. This is why all the major pharmaceutical companies have shut down their antibiotic divisions.

What we need to work towards is a large cash payment on approval of each drug or a guaranteed minimium annual payment. Once we have this we will start to get the new antibiotics we need.

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Why don't we use for medicines the same procurement procedures we use for aircraft carriers? The USG should just hire someone to develop antibiotics for them. It is a matter of national security too - in case of biological attack having a couple more potent will help a lot.

Or having the know how to develop them on demand.

Yes this would be one way of doing it. I think we should try a range of different funding models to see which one works best. What we have learned over the last 25 years is the traditional laissez faire model has failed us when it comes to antibiotics.

One thing I should mention is we don’t have to keep developing totally new antibiotics we can develop antibiotics that are tweaks of existing antibiotics. Antibiotic resistance is an arms race that we can never win, but we can stay ahead with continued investment.

We certainly do have to keep developing totally new antibiotics. Problem is many of the new antibiotics that we have are tweaks on existing antibiotics. We're in such a rush to have something useable that side effect profiles get nastier and bacteria develop resistances to entire families of antibiotics.

The problem is not coming up with new funding models. The problem is getting them implemented.

>What we have learned over the last 25 years is the traditional laissez faire model has failed us when it comes to antibiotics.

What's the best way to quantify the failure? Like a chart showing the bacterial infection death rate for the past 100 years? Costs for the average antibiotic dose over time? Something else? Those data sets seem like they should be available, but are apparently harder for me to find than I would have thought, given the prevalence of all the information available on anti-microbial resistance that pops up for my collection of search terms.

Do you see this new work as a departure from, or a continuation of the antibiotics development of the past?

How fast people are discovering new antibiotics is the important thing, I would think. Assuming resistance is going to happen no matter what, we need to keep discovering new antibiotics at a steady pace to keep up.

Here's one timeline I found in a paper: http://cmr.asm.org/content/24/1/71/F1.expansion.html

I would think it is important to know the magnitude of the problem. Has the number of death from bacterial infections increased from 1 per million people per year in 1990 to 100 per million people per year today? Has it stayed the same? Has it actually decreased over time, and were just trying to be proactive? I'd don't think it is too odd to want to know.

How about a measure of depth of the defence pipeline:

total number of efficacious treatments available per million infections, plotted over time? The million infections might need to be weighted by severity of clinical outcome.

Great, let's get that data too as long as we are at it. Anyone know how to get it?

The problem with this is it is often not known how many other antibiotics might have worked. It might be better to measure drugs known not to work as a percentage of the drugs that work for that class of organism.

Getting this data is likely to be really hard to get and be very labor intensive.

The problem seems to be that an assertion was originally made that we are supposed to accept as true, without any way of quantifying whether it is accurate.

Just got me thinking, shouldn't we try to have a spectrum of antibiotics switched regularly as some form of 'wear levelling' for bacterial resistance ?

>Do you see this new work as a departure from, or a continuation of the antibiotics development of the past?

It is a continuation of some great science that doesn’t ever make it to market. There have been a lot of interesting new antibiotics discovered over the last 20 years or so that just have not been picked up.

What we have learned over the last 25 years is the traditional laissez faire model has failed us when it comes to antibiotics.

I disagree.

Think of it this way. If it were truly laissez faire, then drug makers would charge a price high enough to still make it worthwhile. Unfortunately, the way antibiotics are paid for in US hospitals, the hospitals would lose money each time they used the drug.

Hell, we pay ~$80K to cure hepatitis C (millions have it in the US). If you have an antibiotic that cures a highly resistant infection that happens maybe a few hundred times in the US, why not charge something similar? What is the benefit to society to save someone's life?

> If you have an antibiotic that cures a highly resistant infection that happens maybe a few hundred times in the US, why not charge something similar?

Because a few hundred times 80k is still not much. And even so, many people still can't afford it.

If you can't provide enough value to society that you can spare a few tens of thousands of dollars to cure yourself, are you really worth the cost of developing these drugs, testing them, training doctors, etc.?

All of this over-regulation is why medicine is declining in the first place. That shouldn't justify more regulation.

That easily makes the top 3 list of most sociopathic things I've read all month, and between mass shootings and debates about refugees it's been a banner month for sociopaths on Facebook. Did you intend to measure the value of a human life in terms of enhancing shareholder value or is this just poorly worded?

Some people are only able to reason about things they can measure.

Let's ignore profit for a minute. These drugs still cost money to discover and produce. Who pays for it?

We put a price on human life all the time, not just for drugs.

Agreed and I find this utterly appalling. For me this is a damning indictment of capitalism and a clear indicator that there has to be a better way to handle task prioritization and resource allocation in a modern society.

Is there any system where you can avoid it? Even in a command economy system trade offs have to be made. If you have resources X to spend, you need to figure out what to spend it on. That means you're putting a dollar figure on a human life. I don't see how it could be avoided.

I don't claim to have answers and would definitely support experimentation in this arena. Political systems are certainly ripe for disruption.

The point of providing value to society in the first place is so that people can experience the benefit of it.

> If you can't extract enough value from society so that you can spare a few tens of thousands of dollars to cure yourself

Fixed. I also generally feel casual disregard towards human life and suffering as long as the human in question is not me, but lets call things with their real names.

With a price of drug per year being twice the average income in the richest country in the world - that creates impossible situation by definition for half of its populace.

Also value provided is not always correlated with value extracted - a janitor for a modest fee keeps my house clean. A hedge fund manager ruins the global economy just when I must enter my prime growing years in earnings and make sure I am at a disadvantage at both the cohort before and after me.

Which of those two lives is more valuable to me?

"With a price of drug per year being twice the average income in the richest country in the world - that creates impossible situation by definition for half of its populace."

Even worse. There are a few gigantic outliers at the upper end of the scale. That means that the number of people below average income will be >50%. What you want to check against in such cases is the median (50:50 split by definition).

"Also value provided is not always correlated with value extracted"

That is exactly one of the main problems society is struggling with. How do we even measure value provided? It's a subjective measure to begin with. In the case of the hedge funds manager, it's probably net-negative for most people (but I'm sure her friends would disagree).

Then again. True laissez fair would mean no patents. So I think its fair to assume that it would be radically different in which actors are involved and in which constellations they collaborate. In such a system I wonder if "drug makers" would be able to charge much more than the production cost. Is first mover enough to cover RnD? I suspect not in which case "drug makers" would probably not be "drug inventors"

Many antibiotics are already derivatives of other antibiotics. The problem is that bacteria are developing resistances to whole families of medication. You can tweak erythromycin and get clarithromycin or azithromycin, but that means nothing when the mechanism of action they exploit has been patched in resistant bacteria.

Based on how most government procurement of bespoke products turns out, they would pay far more than it should cost and get a product that doesn't work.

> This is why all the major pharmaceutical companies have shut down their antibiotic divisions.

Also, Radiolab recently noted[0] that antibiotic resistance can often be found in the wild within just a few years after a drug's discovery.

Antibiotic resistance was found in the wild to penicillin before it was even widely used by the public.

Others had a few years (or sometimes months): Streptomycin ~5 years Linezolid ~2 years Clindamycin ~1 year Piperacillin ~1 year Meticillin 11 months

Why burn through 10 years of development for 1 year of sales? It doesn't even take very wide use before resistance gets around...

[0] http://www.radiolab.org/story/best-medicine/

Exactly. If there was money to made selling antibiotics they would have keep investing in this area. They have started again recently, but there is an awful long lead time to develop new drugs - even longer when you have laid off all the people skilled in this area.

The episode took a turn, however, when they looked at Medieval versions of antibiotics -- a treatment for eye sties, I think they discussed -- they found the described treatment was wildly effective.

The researchers they interviewed postulate resistance wanes when a treatment leaves the population for a while.

The conclusion at the end was that it would be beneficial to have a big bevy of antibiotics and such, that we could rotate through as immunity came and went.

In this ^ way, it would seem these pharmas, and the pharma market, needs to adopt a second perspective on antibiotics. They should look at a new drug not for revenues over the next 6 quarters, but over the next 6 decades. In that time frame the drug would hit, be shelved, hit, and repeat.

Perhaps this would be one place that more permissive or advantageous patents would help, by encouraging growth in the antibiotic industry. That probably sounds unpopular given the general "no patents!" sentiment, but I there could be reason in it for at least some period of time.

It's more complicated than that. Just because resistance happens, doesn't mean it happens on a broad scale. A lot of those older antibiotics you mentioned are still broadly used as a first line therapy. Since only a fraction of people are infected with resistant bacteria, they work for most infection.

It's when the first line antibiotic stops working that you need to go to the newer antibiotics.

> This is why all the major pharmaceutical companies have shut down their antibiotic divisions.

No, but the other side of it is that for the money that they had invested, before shutting it down, they got very little at all. That is the other explanation here — that they invested money into antibiotics research and simply couldn't make it work. E.g., http://blogs.sciencemag.org/pipeline/?s=antibiotics

Yes they had invested money and they could not make any money out of antibiotics for the reasons I listed. This is why they shut them down.

There is some evidence that some of these divisions weren’t very good at finding new drugs, but even when they were found they weren’t brought through to market because there was no profit.

More and more it seems that pharmaceuticals are a poor fit for free market capitalism. The basic research is already mostly government funded, they should fund all of it. From trials to sales. Maybe they could use private actors for manufacturing.

I think this would be a very good thing.

It would seem that nationalizing the pharmaceutical market would also be counter to free market capitalism.

The answer is that the government needs to run it in the same way they run the roads and the sewerage, as a tax funded service.

One possible solution would be to split the world into regions, with different front-line and reserve anti-biotics in each region. In other words, antibiotic A would be front-line in North America and B,C & D would be held in reserve for resistant cases, while B would be front-line in South America, C in Europe, D in South Asia, etc. New anti-biotics would be allocated a new front-line territory by splitting existing territories. So when antibiotic X is developed, then e.g. North America is split in to East (uses A) and West (uses X), providing a market for X. This solution also has the advantage that it shrinks the population which is using each antibiotic regularly, increasing its useful lifetime.

Of course, this solution ignores issues of varying toxicity and side effects (not every antibiotic is equally appropriate for front-line use) and anti-trust issues. If an ordered schedule for reserve antibiotics was used, the same principle would apply, just one step farther up the reserve schedule. So, if no one wants to use your antibiotic because it is very harsh, but if your antibiotic is first choice among the harsh reserve antibiotics in some region, it will at least get used some, perhaps enough to pay for development. Anti-trust issues could be dealt with by splitting the regions along jurisdictional lines, or by international agreements. Because this proposal is pro-competition (because new entrants are granted new territories) it also may suffer less regulatory ire than most collusion agreements.

If you dropped the FDA process out of it then progress wouldn't be stifled.

There are millions of people in US with anti-biotic resistant illness.

There are millions of people in EU with anti-biotic illness.

These are serious, life-threatening, life-limiting illnesses where the seller can set high prices.

This is far from "near zero" sales.

http://www.who.int/mediacentre/news/releases/2014/amr-report...

Yes this is because we have not been developing new antibiotics because of the non-use problem. Now of course because all the antibiotic divisions have been shut down we don't have the infrastructure to bring new antibiotics to market at the rate we need. You have to make the decision to develop a new antibiotic 15 years before you need it.

We need to develop new antibiotics before we have a problem and where they will sit on the shelf, rather than wait until we have none and then panic.

Please give a better cite. Yours does not seem to support your claim. The only part of that link that mentions "millions" is

> Treatment failure to the last resort of treatment for gonorrhoea–third generation cephalosporins–has been confirmed in Austria, Australia, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden and the United Kingdom. An estimated 106 million people are infected with gonorrhoea every year (2008 estimates).

Only 1,000 people die a year from gonorrhoea worldwide, the vast majority of whom live outside the US and EU.

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

To the best of my knowledge, the anti-biotic resistant bacteria that currently poses the greatest public health risk is Methicillin-resistant Staphylococcus aureus (MRSA).

> Many of these infections are less serious, but the Centers for Disease Control and Prevention (CDC) estimates that there are 80,461 invasive MRSA infections and 11,285 deaths due to MRSA annually

https://en.wikipedia.org/wiki/Methicillin-resistant_Staphylo...

None of these are millions of people with life-threatening risks in the US.

Try to tell me that if you had gonorrhea you'd be happy to go without any treatment.

Who said anything about being happy about it? You said:

> These are serious, life-threatening, life-limiting illnesses where the seller can set high prices.

This after referring to millions of cases. The response was that the only disease in your reference anywhere in that ballpark is gonorrhea. While I definitely don't want to get the clap, it is none of those things you mentioned.

Parent didn't say that he or people with gonorrhea in general "would be happy to go without any treatment" -- so why do you ask him that?

He merely said that people with such needs are a few tens of thousands, and not many millions, so they don't constitute a viable market.

If your new point is that, "ok, they might not be millions, but they would still pay any price for a treatment", that would also be wrong: They might be WILLING to pay any price, but for most of them it wouldn't be possible to pay that much. There are lots of people that need stuff from surgeries to dental work, that are NOT happy not having them, but that nevertheless don't have them, because they can't afford them -- and expensive gonorrhea drugs wouldn't be much different.

These are serious, life-threatening, life-limiting illnesses where the seller can set high prices.

Unfortunately not. The way that public payers (Medicare, Medicaid) pay for antibiotics levels very little room for high prices. Even private insurance is going in that direction.

If drug makers charged a high price, then hospitals would be left holding the bag.

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