Comment by criley2 | Hacker News Reader

Comment by criley2 | Hacker News Reader

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This is completely wrong.

Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world.

Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans.

Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population.

Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo.

The dose we take is not a "BEST GUESS"

It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo.

It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag).

Source: Drugs: From Discovery to Approval, Second Edition http://onlinelibrary.wiley.com/book/10.1002/9780470403587

Please see papers like-

https://www.ncbi.nlm.nih.gov/pubmed/14714120 No difference in response between people taking 20 mg prozac daily vs. every third day.

Do all 10,000 attempts go through all the testing? Or are many weeded out before $1 billion has been spent?

The $1 billion dollar cost per drug is risk adjusted, so it includes all failed attempts at clinical trials and compounds that didn't make it through pre-trial screening.

Edit: The $1 billion number is meaningless outside the context of large pharmaceutical companies. The cost for phase 3 trials is in the tens or hundreds of millions of dollars so the floor is a wide range and there have been instances of companies getting incredibly lucky and developing a drug for much less than a full billion.

Why are drugs almost exclusively dosed in multiples of 5, ie 50mcg, 250mg? Surely this introduces a margin of error vs the "perfect" dose.

Come on, metabolism itself is reasonably variable even with controlled diet and perfect adherence. In reality, even more so.

Sounds like you don't know what you are talking about. Your source is a book written with heavy influence by the Pharmaceutical industry to justify the obscene costs of their drugs, making billions in profits off of sick, poor people.

You are the one who is completely wrong.

The dosages most certainly do start out with a "best guess" in the pre-clinical phase. For any given drug we would guess at the doses based on our calculations, and give a range on either end. If we thought the effective dose would be 1 mg/kg, we would run an LD50 of doses much higher than that, 10mg/kg, 100mg/kg. Sometimes our guesses would be wrong, and the low dose animals would die as a result. After figuring out a safe dose, we would then split it further into different dosing groups to test the effectiveness of the compound. Most people in the field are underpaid, overworked, and do sloppy work

Please talk to someone who has actually worked in the Pharma research field, they will tell you most of what they do is just guessing.. why do you think only 1 in 10,000 make it through?

It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?

>It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?

We know how antidepressants work, the chemical reaction is well known and can be quantified at different doses. We just don't know why they work because we don't understand why/how the brain works.

Pedantic but important difference.

No, we don't know the antidepressive mechanism of antidepressants, therefore we don't know how they work. Understanding some neurochemical reactions and biological adaptations they cause is not enough. (We also don't have a complete understanding of depressive disorders, we don't really have very effective medication/therapy for many depressive people, etc.)

You and the GP talking about entirely different things. You're talking about how investigators choose the initial dose for the clinical trials, he's talking about the dosage that is actually prescribed by doctors.

Hence the 'The dose we take is not a "BEST GUESS"' (emphasis mine). Unless you're a lab animal or a person in a clinical trial, the does you take is the end result of lots of money spent on first figuring out maximum safe dosages (Phase 1) to prescribing guidelines that doctors are taught (Phase 3).

Antidepressants are a unique group of drugs because the dosage is highly dependent on each person's unique brain chemistry and a huge part of a good psychiatrist's job is working with their patients to find the right dosage and combination. The problem is that many psychiatrists don't have the time (due to insurance billing practices) or the patience to do the work but any decent psychiatrist will tell you that recommended doses for antidepressants are just a safe starting point for most patients, not the dosage that they will eventually find most effective.

For the record, I have worked in the pharmaceutical industry on pre-clinical drug development and Phase 1-3 marketing applications and the GP's description is largely accurate whereas you seem to have a chip on your shoulder. I wouldn't trust a single book about the drug development process that wasn't heavily influenced by the pharmaceutical industry in one way or another just like I wouldn't trust anyone without semiconductor industry experience when talking about Intel's cutting edge fabrication processes.

> Antidepressants are a unique group of drugs because the dosage is highly dependent on each person's unique brain chemistry and a huge part of a good psychiatrist's job is working with their patients to find the right dosage and combination.

How does one accomplish this absent trial and error?

This fact undermines the entirety of your argument.

"Best guess" is exactly what they do.

It is not a guess. It is statistics. Typically, the dose is either effective or partially effective and often on the smaller side as Phase 3 also looks at side effects.

You do know what "unique" means in this context, right? Hint: it means that antidepressants are the exception to my argument because psychopharmacology is so much more dependent on genetic/environmental factors than the rest of the pharmacological field that we cannot draw conclusions on the effectiveness of dosages pre-treatment without spending 100-1000x more time and money on the clinical trials than we do now.

Please take your clearly ignorant bias and anti-pharma prejudice somewhere else - you have no idea what you're talking about.

SSRIs, SSRIs, MAOIs and TCAs all have reasonably well understood pharmacology. As an extreme example, there are very detailed guidelines on how to prescribe venlafaxine, to whom, and who should supervise. You're free to dispute these claims but I think you need to produce more than a blanket dismissal, especially as the OP offers a seemingly reasonable source.

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