EPT1) Establishing a target and find something that can bind to the target. Part 1 Link
2) Preclinical
3) Phase I
4) Phase II
5) Phase III
6) Post-Market or Phase IV
2) Preclinical phase
Basically testing pharmacokinetics(blood levels and duration), pharmacodynamics, toxicity, and ADME in animals. This phase is too see if your drug has the intended therapeutic effect and trying to nail down if your drug is relatively safe in comparison to the disease indication in question. Where is the uncertainty? The animals itself of course! The answer is rather obvious. But if I may repeat my mantra, the devil is in the details. (P.S If you want to work for pharma or biotech, better become detail oriented even if you not naturally one!)
Let me make this clear, animal testing is essential and frankly will be around for the foreseeable future. This is simply because we have no other methods to model the interaction of the drug and a living organism. Generally speaking, the more toxic a drug is, the more likely there is a underlying common mechanism between mice and men. Here is a good view of necessity of animal models
linkie.
A quote from Daniel Engber on the ubiquity on the C57 black mouse.
"So one dark-brown lab mouse came to stand in for every other lab mouse, just as the inbred lab mouse came to stand in for every other rodent, and the rodent came to stand in for dogs and cats and rabbits and rhesus monkeys, the standard models that themselves stood in for all Animalia. But where is Black-6 taking us? How much can we learn from a single mouse?"
Approximately 90% of the mouse genome can be aligned to human DNA and 99% of human genes have an equivalent in mice(Source). But living organisms are just so much more than their DNA[1]. The effectiveness of the animal models varies highly across indications. The predictive value of mouse models on cardiovascular (circulatory), diabetes, and anti-infection indications are not too bad. They are however downright terrible for central nervous system(CNS), obesity, and oncology. It is important to appreciate good pre-clincal methodology when you come across it.
The point is, the only way to tell if you drug is going to work is to just keep moving forward. Other animals models used after the mice, which includes rats, pigs, macaque monkey and dogs. When you test toxicity in dog, the drug is seriously considered for development.
I want to emphasize the pushing forward part for one moment.If you will remember the previous episode, our head scientist submitted our compound into the next development stage. Pharmaceutical companies can have metrics where a group has to submit an X number of compounds within a period for development. Thus the incentive is submit something even if you are not sure about it. The time gap between the chemistry stage and phaseIII/Market approval is large enough where you could be potentially just pass the hot potato down the road. Of course since we are talking about the chemistry stage, most compounds just flat out fail once they are put in mice, and failures at this stage is relatively cheap. However the same incentive structure still exist at the animal testing stage.
An animal clinical development group tested our anti-cancer compounds in mice and xenograft. Let's say this compound successfully reduce tumor size by 30% and induced remission for balls cancer(testicular if you want to get technical). You once again go into a committee and show them the result. You are going to confidently say the results look good and not explicitly mention well mice are bad predictor for the treatment of balls cancer. The committee agrees with our assessment and the compound moves forward to the next phase[2][3]. Joins me in our next episode as our anti-balls cancer compound move into human trials!
[1] Seems rather obvious to mention. But when the human genome project was completed, there was a real sense in the media and in pharma too that we are going to cure every disease known to mankind.
[2] The people on the committee are not stupid, they are generally aware of problems with mice models for oncology(Or they should be aware of it to be more correct). However, we don't have anything else to go on, and there is no reason to kill the compound at this point.
[3] The mindset for using poor modeling(Linkie)
Also if you guys are interested in this stuff. I would strongly recommend In the pipeline. He is a better writer than me and goes into alot more details about every aspect of the pharma industry.
As usual all questions and comments are welcomed.
