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Orphan Drugs (99percentinvisible.org)
64 points by thread_id 33 days ago | hide | past | web | favorite | 40 comments



Excellent article. I had no idea that Quincy was involved in this legislation being passed.

I would like to see more research into diet and lifestyle based approaches to dealing with "orphan" diseases. To my mind, that's a possible path out of this trap. You have to eat anyway. Food chemistry can have substantial impact on the body, especially if you have some anomaly where the body processes certain molecules differently.

I manage my condition with diet and lifestyle. I get attacked and dismissed as a deluded nutter suffering Munchausen for trying to talk about that online. But I don't know what the hell else to do.

The mods on HN have been really great about the situation. I've been thrown off of other forums or told that people violating forum rules to attack me are fine and I'm the problem and I just need to shut up. I try to not push it too much because I don't want to end up locked up in an insane asylum and dead because of it, like Semmelweis.* Though, in my case, dying would most likely be due to being denied the control over my diet and physical environment that makes it possible for me to be drug free and relatively healthy rather than being beaten by the guards and ending up with sepsis.

You probably can't make the kind of money from researching and promoting dietary and lifestyle approaches to such conditions that you can from orphan drugs. I don't personally know how to monetize it at all. When I had affiliate links on my health blog for a particular brand of salt I got attacked for that and told I could not be trusted, I was merely trying to get rich off the suffering of sick people. Having a form of the condition myself hasn't served to give me any credibility.

In the minds of most people, the real definition of CF is what my CF specialist once told me: "People like you don't get well." Since I'm getting well, clearly, I'm a liar who doesn't really have CF.

I don't know how to find a path forward. Maybe the answer is someday I say "Fuck this noise" and stop trying to share what I know and just focus on something that pays my damn bills. But, for now, that idea still rankles.

* https://en.m.wikipedia.org/wiki/Ignaz_Semmelweis


To me, it's not beyond reason that cycstic fibrosis would respond to diet and lifestyle, and is an understudied phenomenon. I see potential rational caveats, and my guess is that these caveats create some jerky knees among other people who are also suffering (and I'm sure, as a sufferer, you know how emotional the experience dismissal is). A few hypotheses:

  - CF responds to diet and lifestyle in some poeple but not others.
  - Time spent with the disease and disease progression is a factor on how well it can be managed without medication.
  - The above things you mentioned (e.g. you actually have another mimicking condition).  If it's something like that, I think you are still operating on good faith and you shouldn't be blown off by other CF sufferers for it... but people are irrational.  Don't confuse this with denial, by the way!  It's simply a rational possibility.
  - The exact *features* of diet and exercise that affect CF aren't well studied/understood and your regiment randomly hits on them.  This reminds me of people who feel better eating gluten free that don't have celiac -- eating gluten free is a diet that happens to incidentally eliminate a lot of other food allergens other than gluten.  That is, you have a false solution to the problem with real solution hiding in it.
In any case, I've been on the "haters" side re: diet and lifestyle preaching so I can empathize there, too. In particular with chronic migraine, there is a granola crowd who has barely suffered an ailment in their life who suggest that "perhaps a better diet and yoga will help". I've reached a point where I want to slap them sometimes; one of my migraine prodrome symtoms is irraional anger and anxiety, perhaps I will someday :-P

Personally, I wish you the best of luck. I suspect it's statistically likely that you'll depend on pharmacutical intervention someday, hopefully, you can delay that is long as possible. I am by no means anti-pharmacutical, but I know from experience that maintaining a long-term drug regiment has it's own problems.

Fuck chronic illness, raise your hand if you're tired of telling people that your illness won't go away, it can only be "managed". Feel as well as you can.


Thank you.

CF responds to diet and lifestyle in some poeple but not others.

I believe there are around 1600 known alleles -- last I checked. That number may have changed. I am no longer on any CF lists. It's too much drama.

Anyway, the mechanism for CF is a defective cell channel. There are various ways the cell channel can be defective. In some variations, it's outright missing.

To my mind, this is sort of like the difference between albinism and being Caucasian. If you don't have the channel at all, I think that's a completely different and more serious problem than if you have the cell channel, but it's wonky in one of a variety of ways.

Time spent with the disease and disease progression is a factor on how well it can be managed without medication.

This makes it very complicated to talk about. CF causes a compromised immune system and malabsorption. I think most of what most people think of as CF is really severe and chronic malnourishment combined with chronic infection. Those pieces need to be redressed to get healthier. Once redressed, it's vastly easier to manage.

If you are Caucasian, you are at greater risk of sun burn and skin cancer. Imagine a society that called being Caucasian Pale Skin Disorder and dismissed the idea that protecting yourself from the sun mattered. This society lives in, say, Hawaii where the Tropical sun is particularly intense and everyone lives in bathing suits. People with Pale Skin Disorder are chronically severely sunburned. Being chronically severely sunburned has a long list of secondary and tertiary problems associated with it, including high rates of death from skin cancer at an early age.

Someone comes along and says that putting on more clothes or moving someplace where the sun is less harsh can clear up most of those symptoms and give you a nearly normal life with the proviso that even elsewhere you should take reasonable precautions.

Everyone laughs and says "Dumb bitch! Putting on more clothes won't cure cancer!"

The above things you mentioned (e.g. you actually have another mimicking condition). If it's something like that, I think you are still operating on good faith and you shouldn't be blown off by other CF sufferers for it... but people are irrational. Don't confuse this with denial, by the way! It's simply a rational possibility.

My official diagnosis is atypical cystic fibrosis. I've had two or three blood tests for the 100 most common alleles. I don't have any of those.

My doctor requested a more comprehensive and expensive test from Stanford. My insurance company denied the request. They had probably already spent at least $25k on me that year according to conversations I had with my sister who had serious health problems of a different sort, civilian insurance and she works at the CDC. I was a military wife. I saw damn few bills. I mostly flashed my ID card and got it for free.

My doctor diagnosed me on the basis of symptoms and medical history. Based on my lifelong history of respiratory infections etc, he expressed surprise that it took so long to get a diagnosis. He felt the diagnosis was correct because I was responding to treatment.

I was previously misdiagnosed as asthmatic. Articles I've read indicate this is a common misdiagnosis for people with atypical CF, who tend to be treated like a hypochondriac and not get identified until late in life. In a nutshell, that's my story.

My best understanding is that I have all the same issues as someone with classical CF, they are just less severe. So most likely the channel defect I have is relatively moderate.

The fact that I can't name my alleles because my insurance company denied the request for the more comprehensive test is one of the reasons I have no credibility on CF lists. Everyone with CF can name their alleles. Except me. So I must be a fake.

The exact features of diet and exercise that affect CF aren't well studied/understood and your regiment randomly hits on them. This reminds me of people who feel better eating gluten free that don't have celiac -- eating gluten free is a diet that happens to incidentally eliminate a lot of other food allergens other than gluten. That is, you have a false solution to the problem with real solution hiding in it.

Well, I kind of randomly stumbled across stuff that helped, then tried to figure out why it helped. Having a diagnosis of CF was enormously helpful in figuring out why it helped and building on my successes. At this point, I think it's very unlikely that it's "coincidence" that it helps, but really due to some other dynamic.

One example: I used to take $300/mo in supplements. Given my diagnosis and the thousands of dollars a month most people seem to spend on maintenance drugs, I figured that would continue for life. Instead of maintenance drugs, I would have maintenance supplements.

I don't take supplements anymore. I think redressing the severe malnourishment reversed a lot of my symptoms. I also think that the normal progression of CF is rooted in a vicious cycle where chemical derangement of the cell promotes more misfolds of the CFTR. So, the sicker you get, the fewer CFTR channels you have at all. The bottleneck gets narrower and narrower and narrower. The sicker you get, the sicker you get.

Reversing the cell chemistry derangement stops that vicious cycle. I can optimize the number of semifunctional CFTR channels I have, widening the bottleneck.

This is known to help. Some drugs help by increasing the number of CFTR channels you have.

There's actually a fair amount of well known stuff that helps. It's just piecemeal and not promoted by doctors as standard therapy. It gets downplayed.

One thing known to help is MCT oil. This is oil high in medium chain triglycerides. It's typically from Palm oil or coconut oil.

MCT oil or coconut oil is well established as therapeutic for people with serious gut issues, not just CF. I once found medical literature online where it used to be prescribed by doctors for various issues, including stomach cancer.

They frequently prescribe ADEKs, a vitamin containing A, D, E and K. These are all fat soluble vitamins. People with CF are typically chronically short on such vitamins.

(IIRC, ADEKs was actually discontinued. Presumably, there's not enough money in it and it's just a vitamin supplement.)

So we already know people with CF significantly misprocess dietary fats and this has significant health consequences. We just haven't pursued that in earnest as a serious therapeutic approach, probably in part because we don't take diet as seriously as we do prescription drugs and in part because there's no money in giving people a list of beneficial foods and a list of foods to avoid.

One of the most significant changes I made was eliminating peanut oil from my diet. After five years of trying to avoid all peanut products, I was able to reintroduce peanut products back into my diet in small quantities, occasionally. I have to buy the "natural" peanut butter. I can't buy the regular peanut butter. I still avoid peanut oil.

I grew up in Georgia, peanut capital of the known galaxy. A lot of American snack foods are made with peanut oil. Chick-fil-A proudly advertises they use only 100% peanut oil. That was one of my ex husband's favorite eateries. I will not set foot in a Chik-fil-a anymore. Even drinking lemonade or eating salad from there tears up my gut because everything from the place is coated with residue from them cooking on high heat with peanut oil.


Another sign that health care and commerce do not mix.

In some countries, there are plans to "regulate", in this case to mandate distributors to keep 4 months of supply. I doubt if that will work.

Instead, like the UK NHS, where the healthcare itself is non-commercial and fair to everyone, the R&D + production of drugs could also be organized much better:

Do the R&D via universities, that should receive grants to develop into directions that are socially wanted, instead of developing more of the same (like high-bloodpressure drugs) just because of commercial interests.

States can collaborate and organize e.g. very expensive high engergy physics R&D (such as CERN) or fusion energy. Why would the same system not work for drugs R&D?

The production itself, completely patent free, can be granted according to demand to commercial companies. These just produce what health care systems order. The states/systems pay a fair price allowing the companies to have a decent profit margin to remain viable, but the current profit margins in the pharma sector are much too high and immoral, since there are people dying because they cannot affort the necessary drugs.

I think this sector has proven more than once, that it is not capable of taking the very high responsbility, but is driven by greed that leads to immoral actions.


Considering most drugs fail to get to market, I’d offer that the profit margins aren’t all that good if you start from scratch.

Saying profit margins are too high is easy if you just count the winners.


Marketing is a larger cost than Reseach for major drug companies.


This trope is always pulled out but it’s wrong. The analysis looked at S&GA which represented far more than marketing.

Second, marketing produces a positive ROI (or why else do it). So you spend $10M on marketing and get more than $10M back.

Third, you can’t sell a drug without some type of marketing. I know HN is full of engineers who build products that sell themselves, but that’s BS. Doctors often have misconceptions or lack information about new drugs and getting someone in front of them to educate them is necessary.


Great, let's outlaw marketing to patients. Then paid experts can deliver independently produced research directly to doctors.


Doctors fall to marketing all the time. Even just hearing something mentioned makes it easier to jump to conclusions and rarely for the better.


Positive ROI relating to prescribing people useless and often harmful drugs. Just look at prescriptions that just happen to fall off after drugs go generic.

People are also buying insurance which is priced based on the assumption people will get useless prescriptions. So, this advertising really adds a lot more costs without nessisarily any net benefits.


What? Prescriptions tend to increase when a drug goes generic, not decrease, since the cost is lower.


Depends on the drug. Many drop off after marketing is cutback.

It’s a question of how many similar drugs are out there.


> Marketing is a larger cost than Reseach for major drug companies.

People on HN love to point this out, as if it somehow implies that companies are wasting money.

Marketing is how companies secure their revenues from the drugs that do make it to market. Without marketing, they'd have even less money to spend on R&D.

(And yes, marketing takes place in countries besides the US. Marketing is more than just consumer advertising).


I think counting the losers is the great rhetorical trick pulled on the public by the pharmaceutical industry.

In what other industry do organizations get away with charging customers such exorbitant amounts of money to cover their failures?


"Counting the losers" is part of R&D. Many companies invest in R&D, having failures is normal. According to Investopia[0], pharma companies float around the top of R&D spending. They indicate the semiconductor industry gets away with charging customers with more R&D spending. (Note, Investopedia doesn't cite any sources, so take it with a grain of salt.)

[0] https://www.investopedia.com/ask/answers/060115/how-much-dru...


GP here. Using throwaways for privacy.

Don't believe the hype. The total R&D cost of an entire industry has a tenuous connection to those for a single product or organization.

The lion's share of early stage R&D in pharmaceuticals happens in academia or start ups. The big players "acquire" the successful ones somewhere around phase II trials.

In the semiconductor industry, like pharma, failed startups go out of business and disappear. Intel would get laughed out of the room if they tried to claim the R&D costs of such failures as their own. Yet for some reason everyone buys this argument from the pharmaceutical companies.


"Me too" drugs are quite useful. Let's say that compound A and compound B both treat your condition. Both have side effects, but there's some difference in the two sets. Or, if we're talking about compound still protected by patent, what if you have a negative reaction to the inactive ingredients in one? Would you rather that patients who can't tolerate side effects just go without?

Serendipity is a real thing too. Nobody started with the idea of creating boner pills or hair regrowth cream when they created Viagra and Rogaine. Both were failed treatments for another condition that happened to have useful side effects.


You're severely underestimating how expensive drug research is. It costs nearly 3 billion dollars to get a drug from zero to market-ready according to the TCSDD.


This often quoted number includes the investments in failed drugs (an outstanding majority) and 1.5B of an 11% cost of capital "opportunity cost" (i.e. money not gained by investing in other stuff).

It is therefore highly misleading when quoted out of context, as it is not the real amount of money that is spent on a single drug.


Huh? Those two things certainly do represent real costs.

If a company spends $2B to develop 5 candidate drugs and four fail, the cost was $2B for that drug. Learning what doesn’t work helps you find something that does.

Second, opportunity costs are real costs, even though most consumers ignore them. You see this when buying a home. People never count the money they could have made by putting their down payment into the market, but that’s still money lost. You can argue 11% is too high, but that’s a different argument.


I understand the numbers, but they are highly misleading, which is my point.

When you say it costs $X to do $Y, including in $X the cost of 20 other times you fail to do some other thing that isn't $Y is unexpected.

Likewise re: opportunity costs. The actual investment doesn't include the opportunity cost. I.e. only around half of that money had to be obtained.

The numbers are meaningful from the capital allocator perspective, which is not the conventional perspective.

The number that people picture when you say "the cost of bringing a drug to market" is ballpark 100-200M.


The conventional perspective seems misleading, then. Saying you can bring a drug to market for a price that doesn't include the costs of failure in finding out how to make the drug in the first place completely distorts the matter, IMO.

Maybe I'm not getting what you think the benefits of not counting research costs across the board are.


Pharmaceutical development is really just throwing mud at a wall and seeing what sticks.

Sometimes, something sticks and you get rich, sometimes it doesn't and you get nothing.

If during one of those failed attempts you came across something useful but not lucrative, I think the cost of bringing it to market should start at that point, and should not include all the trials when you were looking for the cash cow that you had to do anyway. shrug


The date in TCSDD is self-reported by pharma companies. Besides, the data is neither publicly available nor are their methods transparent [0]. A recent peer reviewed study estimates the average cost of a cancer drug at $648M with revenue after approval being $1658.4M [1].

[0] https://www.nytimes.com/2014/11/19/upshot/calculating-the-re...

[1] https://jamanetwork.com/journals/jamainternalmedicine/fullar...


How much of that 3billion goes to the fundamental research vs. the amount needed for regulatory approvals, though? (On average -- obviously it will vary quite widely from one drug to the next and will depend on many factors.)


The expensive bit are the clinical trials. They are required for approval, but they are research.


This is very interesting but it lacks a key piece of information: how is this situation handled in other countries?


In Japan orphan drugs get priority reviews and patients don't pay anything (i.e. government/social security pays 100% for the rare disease). Companies who produce such drugs have almost carte blanche to make any price they want, since "nobody" is directly paying in the end.


>> Companies who produce such drugs have almost carte blanche to make any price they want

That's not really right since it's not open competition.

MHLW sets a price for orphan drugs, which all companies must follow. In practice, the Ministry tends to use global prices as baseline in its negotiations with orphan drug suppliers, through their trade group representatives.


Quite a few countries aggressively nationalize orphan drug production facilities.


Such as?

Europe has their own version of orphan drug incentives, as does Canada.

I’ve never heard of a country nationalizing orphan drug production facilities.


India for one.


this is an awesome look into the economics of curing diseases that cannot benefit from economies of scale. Its unfortunate the rare diseases end up having such expensive cures but on the other hand people can develop cures for disease that otherwise would be uncurable.

interesting double edged sword


This discussion is Great! Clearly this is a difficult topic that lots of people feel is important. I find it interesting that there is so little consensus in the comments. To me that is a really interesting question and discussion.

I wish I had a good answer.


> one rare disease drug came out with a price tag of $150,000 a year — a lot of money.

If there are just 100 patients out there that's not a lot of money for the company in the end. Cancer drugs are way more common and yet remain expensive, too.


For orphaned drugs, companies have a monopoly status on it and clients litteraly can’t forgo buying, and will do whatever research is needed to find the product. There is no nudging or bribing the doctor or whatever is needed to take an edge.

Considering it’s long argued that one of the main cost of a drug is marketing [0], for any drug where it’s significantly more than 100 people we shoudn’t get these crazy prices.

[0] http://naturalsociety.com/research-development-new-drugs-not...


You are missing a major point. Lots of people who have rare disease are not even aware they have them, or not even diagnosed because their local doctor has never seen it before and mistook it for something else.

So yes, you still need "marketing" to spread awareness for rare diseases, because they are, well, rare.


Yet the CDC is effective at spreading awareness of common diseases. Why do this via drug marketing?


Cystic fibrosis is a "rare disease". A quick search gives me this blurb:

Very rare (Fewer than 20,000 cases per year in US)

My recollection is that I have heard that there are 30k CF patients in the US. I've also heard long time members of the CF community snort at that figure and say "They've been saying the same thing for decades while the list of alleles known to cause it grows longer."

It's genetic and incurable. So you need treatment for the rest of your life once they ID you.

I've seen articles that suggest that standard conventional treatment is anywhere from $100k to $250k annually. I've also seen articles that suggest it's called lot less than that get discussed on CF lists by people going "Where did they get their numbers? That sounds too low. My expenses are x, y, z."

https://www.wsj.com/articles/vertex-gets-fda-ok-for-cystic-f...

Vertex $259,000 Cystic Fibrosis Drug Gets FDA Approval Orkambi treats most common form of the lung disease

Vertex already sells Kalydeco, which treats a different genetic type of cystic fibrosis and has an annual price of $311,000 per patient in the U.S.

I know of a teenager on Okambi in another country. So the market for Okambi is not limited to the thousands of people in the US who have CF. Granted, you have to get separate approval in different countries and that's a genuine burden.





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