Different approach for drug approval

[dopamimetic]

Okay, it appears to me that currently the consens in pharmacology is to have one drug that is as specific as possible to a certain target, e.g. very selective SSRIs, GABA-A subunit agonists, mu opioid agonists etc. Then, in some cases, it is being tried to put multiple targets into a single drug (e.g. vortioxetine, SSRI and 5-HT subtype agonist, neuroleptics with additional H1 or 5-HT antagonism etc). And to get a substance approved, it must show superior efficacy over currently available medicines - in a single substance. This concept appears to be significantely flawed to me.

Imo we should get away from that "one drug solves it all" thinking, and use a completely different approach - of course it is always the best to have upmost selective drugs (where this is possible), but this doesn't match with the expection of being superior to treat a certain disorder. Rather we should have kind of two-step approval. Step one concerns the safety of a given substance, e.g. it being non-toxic to organs etc. Step two involves treatment regimens that should be fine-tuned to specific subtypes of disorders and individuals, independent of if one or multiple drugs in varying dosages are required.

The best example that comes to my mind is for pain treatment, like a mu agonist and a NMDA antagonist - a pair that has shown to be superior to each one. But unless a single drug with optimal agonism:antagonism ratio could be found (something that very probably greatly differs between individuals nevertheless) we won't see this approach to get used widely because it is hard to make big money out of it unless we have a really rare disorder (why is Nuedexta approved and memantine/morphine etc. not?) Or for depression - if the use of a SSRI appears to have potential, then instead of developing something like vortioxetine, rather use a very selective SSRI and depending on the individual, some selective 5-HT agonists/antagonists, and if insomnia is present, use a selective H1 antagonist instead of adding quetiapine with its bunch of side effects, just look at constricted nose - something afaik many get from very low dosages of quetiapine - (okay, this combo would be possible e.g. hydroxyzine but Big Pharma teaches the docs to use quetiapine because of monetary reasons).

It really frustrates me when I think about all these innovative, promising approaches we have seen recently, like selective 5-HT2A inverse agonists, whatever, and they failed in "simple" trials to show superior efficacy. So they get withdrawn, and nobody is able to profit from all the efforts made to develop them, "even" if it was only a minority who would get actual benefits - but I'd bet that used in the right combinations, such selective drugs would indeed be very effective.

Well, probably this is all nothing new for you educated professionals, but likely many us are catched in this "we need one superior drug to treat a specific illness" thinking - including politicians etc.

I mean, everybody thinks that pharma companies are just after money, what is quite obvious. But the current situation makes them rather loose much money from the trialed and dumped drugs .. it would be the less worse solution for all if we could get away from what we have at the moment ...rigid systems fuck the world up..

 

[Kittycat5]

They have been talking about this patient specific or targeted medicine since I was in pharmacy school 20 years ago. Advances in genetics, medicinal chemistry, the biology and chemistry or proteins and computation is getting us close but we arent there yet. And you are thinking of small molecule drugs which are nearing the end of their lifespan. Biologics are here now and the future of pharma almost certainly is biologics that are much more specific to a tissue or disease or patient.

I do wonder how they may patent such things but I am sure they have plans.

 

[serotonin2A]

There isn't really a consensus that drugs should be as selective as possible. In fact, some drugs (for example vortioxetine) are designed to hit multiple targets. The reason why selective drugs are preferred is that they tend to have less side-effects. The primary goal of drug development is to find safe and effective drugs. It doesn't matter if efficacy is due to a single target or multiple targets. In fact, you don't technically have to know the target of a drug to get it approved.

The approach you are arguing for -- using combinations of drugs or adjunctive treatments to improve efficacy or reduce side-effects -- is currently being pursued by pharmaceutical companies. Unfortunately, there have been several notable failures. Acadia's drug pimavanserin was in trials as an adjunct for use with risperidone , but it wasn't particularly defective. Oxytrex, ALKS-4561 (buprenorphine + samidorphan combination), TC-5214 (mecamylamine used as an adjunct for antidepressants) are all other examples of past or current failures. A few decades ago, there were attempts to develop the combination of a SSRI and a 5-HT1B antagonist as a rapidly-acting antidepressant. But that approach failed in clinical trials.

The reason why a memantine/morphine combination pill isn't being pursued is that you can already prescribe memantine and morphine to patients. Trying to put both drugs in a single pill is ultimately a bad idea because it ties patients to a very narrow range of doses for both drugs. First, there is probably not one single optimal ratio of memantine and morphine that works well for all patients. Second, morphine dose requirements vary widely -- some patients will need low doses of morphine and some will need high doses. The latter situation is especially true for patients with severe pain or who have existing opioid tolerance. So there is a risk that patients would have to overdose on memantine in order to achieve adequate pain relief. Of course, you could also prescribe additional morphine pills (without memantine), but at that point you might as well just separate the morphine and memantine into individual products, which is the current situation.

I think it would be a bad idea if the only requirement for drug approval was safety. The whole basis for pharmacotherapeutics is that they are a trade-off between the good and bad effects that come with exposing patients to drugs. There are very very few substances that are safe enough that they will never cause harm to patients. Although "do no harm" is not technically part of the Hippocratic Oath, it is a general principal of modern medicine that patients should not be exposed to unnecessary risks. The idea of approving medications that have no demonstrable beneficial effects in patients runs counter to that. I can also think of two other problems: One problem with having ineffective mediacations on the market is that some patients would receive those drugs instead of being prescribed medications that are actually effective. The other problem is that patients still have to pay for ineffective medications -- we would be going back to the era of snake oil salesman where patients spent huge sums of money on medications that did them no good.

I understand why at first glance it would seem useful to approve multiple selective tool compounds that could be mixed and matched by psychiatrists in individual patients. The problem with that strategy is that it isn't evidence based medicine -- you end up exposing patients to lots of ineffective drugs, some of which may cause disability or even death in an individual patient. Even if you know that a drug is relatively safe from clinical testing, that doesn't mean that a drug can't produce severe side-effects in some individuals.