Is the pharmaceutical industry rolling out medicines on a regular basis?

[aced126]

This might not be for this section so a mod can just move it if deemed appropriate.

Anyway, I was reading this article: http://www.forbes.com/sites/simonki...ing-drugs-of-all-time-humira-joins-the-elite/

The 6th best selling drug in the world is Ablify (aripiprazole) with over 7 billion usd in sales. Seroquel and Zyprexa are also in the top 20, both of which have surpassed 5 billion usd in sales. This is for a disorder which affects 1% of the population. Furthermore, the mode of action of these drugs aren't completely understood (like they are for most other drugs in that list). Obviously neurological disorders are more complicated in itself, but I still think it says something considering that we have such good drugs for most conditions but for schizophrenia they are poor in comparison. I don't know why further research (LOADS of research) is going into this; 3 top 20 meds for this disorder indicates a huge gold pot for pharmaceutical companies.

Is it possible that (similar to how Apple supposedly works, but on a larger scale) the pharmaceutical companies do in fact know the precise mechanism of action of their drugs but they conceal them so they can slowly release better derivatives for more money? I guess the same thing can be said about depression (and many more disorders); only a few SSRIs exist, once again with a supposedly poorly understood MOA.

Obviously it would be wrong to do so morally but it makes sense if one wanted to profit the most. They could essentially make a timetable over the next 20-50 years where they know exactly what they're going to push out and when. Obviously this seems rather difficult, and if this had been happening so far then it would be likely there would be at least 1 whistleblower. My only explanation is that some of the companies do have (secret) labs where far superior workers are making drugs for these kinds of disorders at a much faster rate, and eventually (when the time comes) normal chemists will be instructed to synthesize the compounds already discovered secretly many years ago, to which the biologists report amazing activity.

If they did push out a drug which fully worked against depression then that one would sell well but what do they sell next?

 

[Xzbtya]

I had a list of drugs approved for 2014 by the FDA and almost none of them were antidepressants. There was one sedative drug approved that was an orexin antagonist. The others were for various conditions that really don't have to potential of being major block busters. Many drug companies are losing money because they are releasing better versions of current drugs (better in the sense of side effects, risk factors, etc.) but insurance doesn't want to pay for it because almost equally effective generics are available. I find the scenario unlikely as drug company values and their stock prices tend to be some of the most volatile around. If the FDA doesn't approve a major drug the company is banking on, they are essentially fucked after dumping millions in clinical trials.

 

[dopamimetic]

The 6th best selling drug in the world is Ablify (aripiprazole) with over 7 billion usd in sales. Seroquel and Zyprexa are also in the top 20, both of which have surpassed 5 billion usd in sales. This is for a disorder which affects 1% of the population.

Whoa, that's really crazy. I mean it is odd enough to use Seroquel for insomnia, but this is low dose and wouldn't push the drug into such a high position. We just don't have this much schizophrenics, or...!? Why do people take dopamine antagonists when they don't really need them? And no antidepressant, anxiolytic or psychostimulant in these top 20 ... would have thought that Concerta (or Adderall in the states) was generating as much revenue as Seroquel.

The whole system is flawed. The industry has to push things like escitalopram and eszopiclon to get the money to try to get some other drugs approved etc ... in my eyes the approval process is much too expensive, I can't tell about the process itself but probably also too bureaucratic and complicated. Why on earth did they approve this orexin antagonist (there was a thread about it on bullfight, it has ugly side effects, hangovers etc. and is no better than any of the other sleeping aids) when other really innovative things have such a hard time ... but what I find interesting (albeit few people seem to use it) is this flibanserin, Addyi, for girls with hypoactive sexuality..

Also don't know about the states, but here in Europe there is every year less and less state funded research, this raises 'corruption-like' behavior e.g. those profs who are known to make these results in studies that the industry is after, get the funds and not the best ...

 

[atara]

Is it possible that (similar to how Apple supposedly works, but on a larger scale) the pharmaceutical companies do in fact know the precise mechanism of action of their drugs but they conceal them so they can slowly release better derivatives for more money? I guess the same thing can be said about depression (and many more disorders); only a few SSRIs exist, once again with a supposedly poorly understood MOA.

In order for this to be possible, they would have to be colluding on a grand scale. Competition means that any pharma company who can release a better drug will push its competitors out of the market and get rich, so you expect them to do their damnedest if they haven't all secretly agreed not to. Comcast can get away with it because they have a monopoly.

 

[Kittycat5]

You are absolutely correct in your thinking of the pharmaceutical industry timing when their next drug should hit the market, but think your logic behind why they do so is a bit off. In the age of small molecule blockbuster drugs, the MO of big pharma is something so predictable and repeatable, it really is laughable. They first come out with some drug in an immediate release form that often is dosed more than once daily. As that patent expires, they then release an extended release form and perhaps as the ER form loses its exclusivity, a controlled release form. They market this as a way of enhancing compliance by decreasing how often a patient needs to take their meds and thus be less likely to forget to take it. But it in reality is nothing more than a profit grab. If making it easier for patients to remember to take their drugs on time, why not go directly to an ER or CR form?

Alternatively, they will take a racemic mixture, find out which enatiomer is the active one, and put that one on the market as the racemate goes off patent (think Celexa vs Lexapro). Again, to the public they say the non-racemic mixture is better but this time their reason given is usually a decrease in side effects but money is the true reason. Pharma also will come up with a completely new dosage form (orally disintegrating, powder, transdermal patch any many others) for old drugs to extend their patents or combine their drug with a different agent that treats the same disease but is now available as a generic. This is the case with nearly every oral antidiabetic drug that will add metformin to whatever the newer drug is.

But their two dirtiest tricks pharma plays is legal challenges to defend their patents against generic competition and seeking new indications. As drugs come close to the time when generics will be allowed, you can bet your house that an army of lawyers will be on the job trying to hold back the competion. Often this simply means paying the generic company that has first rights to sell their version of a drug to actually not sell it. But it is often comical the lengths big pharma will go to when they actually need to defend their patent in court, not just pay hush money. When Prilosec/Losec was about to be up against generic competition, the lawyers tried to argue that the color purple was somehow covered by their patent. I know all this is a bit off topic, as its more about hurting the consumers rather than drug discovery, but it is just typical behavior of big pharma, it goes a long way to show just how insane their tactics are.

But the most tragic of all is when new indications are sought to extend the patent. I can live with new populations of adults being the targets of this, but not only are children becoming more and more the target, pharma is actually incentivized by the FDA to do so. If the pharma giants do successful clinical trials in pediatric patients, the FDA rewards them with the wonderful gift of 6 months of patent extension. So basically, because FDA saw deficiencies in the number of drugs actually approved to treat kids, the drug companies will get 1/2 year of profits by getting their potentially harmful drugs in the pediatric population approved based on relatively short studies. But once its approved and barring withdrawal, that indication is there to stay and doctors will feel much less anxiety in prescribing it.

So we are in full agreement in the idea that pharma times their release of drugs to maximize profits, but I do protest against the notion of concealing some magic cure drug to whatever condition is on the table. If such a drug was discovered, most would surely bring it to the market and quickly. They could in theory, have the sole right to sell the best drug ever for 20 years and utilizing any of the strategies above, add perhaps five extra years of exclusive rights. And being a mini-monopoly, the originater can set the price as they see fit. The new Hep C drugs are a great example of this in action. Not only do they have incredibly high cure rates, the length of therapy and side effect profile is very manageable, and most importantly cost 30 grand or more for a course of treatment.

So the best in show type of drug not being available isnt some grand conspiracy to keep people just sick enough to have to use an inferior drug and its sucessors to ensure the money will be flowing for years to come. These drugs and diseases many times are too complex to fully understand and exploit to come up with even better therapies that literally can change or save the lives of millions of people.

So while it may be a goal of the pharmaceutical industry to develop a drug that changes the world, it is often unattainable. So they stick to what they know. You mentioned how three of the top 20 drugs sold in dollars are for small populations. But you missed a few key reasons why this, and current R&D is geared towards producing similar drugs, but distinct nontheless. First is the fact that drugs like atypicals have multiple on and off label uses which increases the number of people who are candidates for receiving one. Second, you need to understand that is the cost of these drugs (which can be > 1000 dollars per 30 units) and not the total number of scripts given that is the determining factor. Is it really any wonder why the drug companies would be eager to enter a market like this? Even if your new drug is inferior to current ones, as long as it gets approved, you can send your sales, marketing, and medical liasson units out into the field to "educate" patients ond doctors on why this $1200 copycat is the right choice for you or your patients.

At last, which is a bit trivial, is simply that is old data. All three of the atypicals now have generics and will not be on a newer list. This further reinforces the notion that high cost rather than rx volume is why they are in the top 20. I also think you overestimate how good the non-psych drugs are at treating some of the conditions in which they are used. Several may actually be worse.

To summarize; it is well known that drug companies are excellent at timing release of "new" drugs and any reason they give other than financial gain is propaganda nonsense. But the quest for the perfect drug isnt simple myth, just hard to do. So pharma tends to ride the coattails of each other, producing drugs that treat conditions they know the market can withstand huge prices and grab some market share through ruthless marketing campaigns. And as the article mentioned, biologics are the wave of the future which further makes the water murkier. The days of a Lipitor dominating the sales lists are nearly over.

 

[aced126]

Cheers for the response. I don't think companies can do the enantiomer trick anymore. I think FDA has made it that any drug going into trials must be in its single isomeric form (unless both isomers are proven to be important to activity).

I agree biologics are becoming more and more prevalent. However I don't think small molecules are going anywhere at least for a while. Especially for neurological disorders where biologics are inappropriate for obvious reasons.

 

[dopamimetic]

If they did push out a drug which fully worked against depression then that one would sell well but what do they sell next?

I really, really hope that we're getting close to such a thing with all the research about ketamine / glutamate etc. and then it would also be worth the money (at least in comparison) but somehow I think we'll still need many years to go down the road.

But yeah, the psych drugs sector is somewhat limited by prohibition. They could earn billions with things like the proposed 'synthetic booze' and all that, what the shady RC vendors are doing currently ...

Anxiolytics that don't cause dependence. Nootropics. Better psychostimulants (a topic where I really miss research and new developments) and ADHD treatments.

Cancer and HIV reversing drugs. And of course something that reverses aging (and would bring everything to a new level in society ......)

 

[serotonin2A]

I wouldn't consider developing single enantiomer drugs as being a trick. Often the distomer is a source of off-target effects and side-effects, so it makes sense not to give them to people. But no drug company is going to go for the eutomer initially, because it is almost always more complicated and expensive to produce a single enantiomer. Most drugs fail at some point during the development process, so drug companies have no reason to start development with the more expensive eutomer if any given drug is almost certain to fail. And then once you've started development of a racemic drug, and made it to phase II, you can't just drop everything and start over with the eutomer.

The only way that developing the racemate first and later the eutomer could be considered unethical would be if the drug company started the development process knowing that either a) the drug would definitely be approved, or b) that the distomer is toxic. But since most drugs fail, drug companies haven't really been able to plan in advance that they will keep the eutomer in reserve for use after patent rights to the racemate expire.

Regarding the OPs post, drug companies have to disclose the identity of the chemist who invented a drug on patent filings. So how would it be possible to maintain secret laboratories without loosing IP rights? The exact events that led up to the invention of a new drug are often the subject to discovery in patent lawsuits, so everyone involved in drug discovery keeps detailed lab notebooks.

You also seem to be under the impression that the current generation of antipsychotics are perfect, while in truth they leave a lot to be desired. They don't treat all the symptoms of schizophrenia (especially negative and cognitive symptoms) and they can produce severe side-effects. So there is definitely a need to develop new drugs, and to find new therapeutic targets.

 

[manboychef]

I wouldn't consider developing single enantiomer drugs as being a trick. Often the distomer is a source of off-target effects and side-effects, so it makes sense not to give them to people. But no drug company is going to go for the eutomer initially, because it is almost always more complicated and expensive to produce a single enantiomer. Most drugs fail at some point during the development process, so drug companies have no reason to start development with the more expensive eutomer if any given drug is almost certain to fail. And then once you've started development of a racemic drug, and made it to phase II, you can't just drop everything and start over with the eutomer.

The only way that developing the racemate first and later the eutomer could be considered unethical would be if the drug company started the development process knowing that either a) the drug would definitely be approved, or b) that the distomer is toxic. But since most drugs fail, drug companies haven't really been able to plan in advance that they will keep the eutomer in reserve for use after patent rights to the racemate expire.

Regarding the OPs post, drug companies have to disclose the identity of the chemist who invented a drug on patent filings. So how would it be possible to maintain secret laboratories without loosing IP rights? The exact events that led up to the invention of a new drug are often the subject to discovery in patent lawsuits, so everyone involved in drug discovery keeps detailed lab notebooks.

You also seem to be under the impression that the current generation of antipsychotics are perfect, while in truth they leave a lot to be desired. They don't treat all the symptoms of schizophrenia (especially negative and cognitive symptoms) and they can produce severe side-effects. So there is definitely a need to develop new drugs, and to find new therapeutic targets.

so like the antipsychotics tend to cause more word salad and involuntary movements (forgot the term for that).

Personally, I am angry at big pharma for releasing cures to hep c but pricing it out of the range of people that really need it. I guarantee this is going to be one of the drugs they pay off generic companies not to produce, and then change around the formulation to keep the patent for a while.

I have tried interfuron and believe me, it made me sick and my hep c came back with a vengence. In fact, the side effects from the shots were worse than what I experience from the hep c and I only really had about three or four symptom free months after that. It seems like after that round of medications (including ribovarin with the pegylated interfuron) my symptoms accelerated the deterioration of my liver.

 

[serotonin2A]

so like the antipsychotics tend to cause more word salad and involuntary movements (forgot the term for that).

Personally, I am angry at big pharma for releasing cures to hep c but pricing it out of the range of people that really need it. I guarantee this is going to be one of the drugs they pay off generic companies not to produce, and then change around the formulation to keep the patent for a while.

I have tried interfuron and believe me, it made me sick and my hep c came back with a vengence. In fact, the side effects from the shots were worse than what I experience from the hep c and I only really had about three or four symptom free months after that. It seems like after that round of medications (including ribovarin with the pegylated interfuron) my symptoms accelerated the deterioration of my liver.

The atypical antipsychotics tend to cause metabolic syndrome symptoms, like weight gain and diabetes.

RE hep C treatments, there really isn't an alternative to the current pricing scheme. Treating hep c over the entire course of the illness is very expensive (chronic treatment with medication, progressing to liver transplant), and has other hidden costs, like lost productivity and reduced quality of life. So the new drug is much cheaper, even though it is expensive per dose. The problem for the drug company is that it probably cost a few billion dollars to develop the drug and get it approved, so they have to pass that cost to their customers. Normally they would do that over the course of years -- but this drug is only taken for a relatively short time.

I know that it sucks not to be able to affort the treatment, but I don't understand what you think they should be doing differently. For almost every branded drug that it is sold, there are people who can't afford to buy them even though they are essential. This is exactly the reason why health insurance exists -- it is often impossible for individuals to cover expensive treatments.

 

[aced126]

I thought they develop the drug as the racemate, and then start to test it and so on. But if you actually want to sell it and it has reached the stage where it's considered effective and a very possible candidate to go on the market, then you would need to figure out which enantiomer is the most effective.

Sorry, I actually had in mind that the antipsychotics weren't perfect by any means, but big pharma has 5 or 6 more antipsychotics, each one getting better than the one before, which they plan to release over the next decades or so. On thinking further about this I realise this is pretty unlikely though.

 

[serotonin2A]

I thought they develop the drug as the racemate, and then start to test it and so on. But if you actually want to sell it and it has reached the stage where it's considered effective and a very possible candidate to go on the market, then you would need to figure out which enantiomer is the most effective.

Sorry, I actually had in mind that the antipsychotics weren't perfect by any means, but big pharma has 5 or 6 more antipsychotics, each one getting better than the one before, which they plan to release over the next decades or so. On thinking further about this I realise this is pretty unlikely though.

The argument can be made that they should be developing drugs that way -- ie, all drugs should be sold as the eutomer, if possible. But traditionally drug companies and the FDA didn't pay much attention to that issue. It isn't black and white; it is not necessarily trivial to scale up the process of preparing an entantiopure pharmaceutical drug. For some drugs it may actually be impossible to scale up the preparation.

There may be 5 or 6 antipsychotics in the pipeline, but distributed over 5 or 6 drug companies. That is important to consider -- you are talking about several companies that are competing for market share. The problem with drug development is that all of those drugs could fail in stage II or stage III testing. They are going to need 5 or 6 candidates just to get 1 or 2 drugs approved.

A good example is promaglumated methionil!! Lilly certainly had high hopes for that drug, and the mechanism in general, but it flopped...

 

[dopamimetic]

An interesting one I have to think about is methylphenidate. They launched Focalin (d-MPH) with huge efforts in 2011 and on the paper it looked promising, more selective and less peripheral stimulation etc - but the real world experiences differed greatly between people. For me, d-MPH is really inferior compared to the racemate and I think to remember some recent assay stating a much higher NET affinity than initially thought. Others reported increasing tolerance, and anxiety issues (like me) too ...

involuntary movements (forgot the term for that)

Tardive dyskinesia?

Sorry, it's Christmas, I'm alone and bored but nevertheless positive ... crazy just that loneliness is killing me ...

 

[sekio]

Far fewer novel small molecule CNS drugs are developed and approved on a yearly basis than you would expect. So "patent busting" extensions such as changing formulations (e.g. oxycontin) or altering the chirality (Focalin, esketamine), or even conversion to a prodrug form/better absorbed salt (Vyvanase, ibuprofen sodium) are rather common because it allows the effective extension of a drug's patent lifetime.

(If you look at the FDA's list of new drug approvals, quite a few of them are biologicals in this day and age. Lots of antibodies and immunoglobulins and the like)

The problem with drug development is that all of those drugs could fail in stage II or stage III testing. They are going to need 5 or 6 candidates just to get 1 or 2 drugs approved.

This, this, a thousand times this. If you look at the percentage of drugs that are developed to the "stage IV" phase - e.g. release to the public - it's a tiny fraction of those developed in intial screening assays.

Just because you have a dozen drugs in the pipeline doesn't neccesarily mean that any of them will be approved. Now amortize in the cost for bringing those drugs to stage 2/3 trials...

Curiously enough I recall reading that the fraction of costs in a commerical medicine devoted exclusively to R&D is in the single digit percentage. So when you read about a blockbuster drug making billions a year, just keep in mind that the guys who came up with the chemistry are usually only making a few thousand at maximum.

 

[Kittycat5]

I dont necessarily disagree, serotonin2a, that the actual development of enatiopure drugs is ethical. I guess my whole tone in my post made it seem that way. But I do believe the promotion of these drugs is pretty close to breach of ethics. The IR to ER is probably a better example of pharma marketing a "new" drug solely as a benefit to patients and not simply as a money play. But I doubt if say, Forest Pharmaceuticals was able to have their patent for Celexa forever, Lexapro would never had seen the light of day. I firmly believe that the pharmaceutical industry's most noble endeavor is bringing new drug entities to the world. It is the rest of their tactics that I have concerns over.

Aced, I am not sure what you said about single enatiomers is true. I know FDA has given guidance to drug companies saying to make sure you are doing tests on the racemate and individual enatiomers and has been widely adopted, but not sure if there is anything binding saying it must be done. If you know, could you link a reference so I can look it over?

 

[dopamimetic]

Somehow I happen to find it unfortunate that so many drugs fail during stages II / III - I mean when there are true serious adverse effects of course these have to go off the shelf, but people are so different and the government must accept that - the more choice we have, the better ... I am a true advocate of choice. Hate it to see the usual diagnosis -> 1-3 drug classes and out of them 1-3 currently popular drugs.

Know that health is nothing to play with. But we have all these adverse effects happening already, I think to remember that (mis)medication is in the top 3 of causes of deaths.

Didn't try it yet, but I think Vyvanse is a good thing actually. They should approve isopropylphenidate now.

 

[aced126]

I'll try find a reference.

 

[aced126]

Curiously enough I recall reading that the fraction of costs in a commerical medicine devoted exclusively to R&D is in the single digit percentage.

Wow, that is just wrong and should change. It is ridiculous how so many disorders could have had effective treatments right now if more money was put into R&D.

 

[aced126]

http://www.amazon.co.uk/Introduction-Medicinal-Chemistry-Graham-Patrick/dp/0199234477

On page 275, there is some relevant information on chiral switching. You might have to click the "surprise me" button a couple of times to land the relevant chunk of pages. It reads "By switching to the pure enantiomer, companies can argue that it is a new invention and take out a new patent. However, they have to prove that the pure enantiomer is an improvement on the original racemate and that they could not reasonably have been expected to know that when the racemate was originally patented."

I think in this day and age it is common that except for special cases (maybe MDMA as the most famous example), one enantiomer is going to be more effective than the other.

 

[manboychef]

The atypical antipsychotics tend to cause metabolic syndrome symptoms, like weight gain and diabetes.

RE hep C treatments, there really isn't an alternative to the current pricing scheme. Treating hep c over the entire course of the illness is very expensive (chronic treatment with medication, progressing to liver transplant), and has other hidden costs, like lost productivity and reduced quality of life. So the new drug is much cheaper, even though it is expensive per dose. The problem for the drug company is that it probably cost a few billion dollars to develop the drug and get it approved, so they have to pass that cost to their customers. Normally they would do that over the course of years -- but this drug is only taken for a relatively short time.

I know that it sucks not to be able to affort the treatment, but I don't understand what you think they should be doing differently. For almost every branded drug that it is sold, there are people who can't afford to buy them even though they are essential. This is exactly the reason why health insurance exists -- it is often impossible for individuals to cover expensive treatments.

check out what australia is doing. Like polio in the states, or rubella.....