Let me make a few things clear about the bio-pharmaceuticals industry.
Manufacturing an innovative drug is an incredibly complex process. There are thousands (literally) of moving parts. The part you see is only the tip of the iceberg, and if you are like most consumers, you ignore even most of the tip.
What you pay for (mostly), when you buy a drug is not the pill or protein itself. That costs from a few bucks to a few hundred dollars to produce. What you are paying for is the little slip of paper you likely throw out or ignore called the "package insert". That represents 15 - 20 years of testing that gives your doctor, and more importantly the FDA, the confidence to give the drug to you and know that the harm that this pharmacologically active poison is probably (highly probably) going to poison what we want it to, and not ... well ... the rest of you.
I gave up arguing with someone in another thread, but let me be clear in this one: every drug sold causes harm.
Every one. There is no "safe" drug. That is why you will never see a legitimate drug being sold as "safe and effective". It's always "effective" caveated by that laundry list of side effects that people like to lampoon in fake drug ads. There is a good reason for this. I repeat myself: every drug causes harm to
someone, somewhere, almost always multiple someones. The question the FDA decides when approving a drug is: "do the chances of doing benefit with the drug outweigh the chances of doing harm?". Different people can have differing opinions on this.
This BTK inhibitor that Pharmacyclics is selling? It's going to cause an infection in someone who has already been weakened by cancer, and that's going to kill them. I can almost guarantee that. But that effect is
extremely rare, and in some cases it clears cancer that was resistant to literally every other treatment, in others it boosts the efficacy of current drugs to put people in remission who would otherwise have needed months or years more conventional treatment. It saves
many more lives than it takes. That is the calculus that adults use
every time they put a pill in their pie hole.
What?
You mean you don't consider the increased chance of getting an ulcer or a heart attack every time you pop an Advil?
Read the goddamn package insert for once, and pay especial attention that that black box label that illuminates the most dangerous side effects.
According to the Advil® Drug Facts, patients should not use ibuprofen right before or after heart surgery. Risk of heart attack or stroke may increase when used at higher doses or longer than directed. Patients are directed to ask a doctor before use if they have high blood pressure or heart disease.
Bold is mine.
OK, what does this have to do with Pharmacyclics?
Well, in order to get to the point where the company and the FDA agree on that package insert, a lot of stuff had to happen first.
A new drug doesn't fall out of the air. Big Pharma doesn't synthesize a bunch of chemicals and stick them in sick rats to see which ones work. That would cost so much they'd all be out of business in a year.
The first step in making a drug actually begins in Academic labs, although Academics are generally totally inept at any of the other steps of making drugs. What a drug maker needs first is a
target. Some chemical process in the body that has gone wrong and is causing a disease.
In cancer, cells multiply out of control. That happens all the time. You likely have several forms of cancer cell in your body, right now. However, the immune system picks up on these renegade cells and kills them before they can clump together and form a tumor. Once in a while, one of these cancer strains mutates a defense against the immune system, and evades what we call "immunoediting". Now we have two mutations: out of control cell division (proliferation), and immune regulation. Some tumors develop other mutations. They divide quickly, so they need a lot of oxygen and nutrition. The tumor actually causes new blood vessels to form to feed itself (angiogenesis).
So just think. I've broadly outlined three possible targets for an anti-cancer drug. One, stop the proliferation - kill the fastest dividing cells (or stop the process by which their divide at such a rapid rate), and try to leave as many of the rest as alone as possible. Two, cut down on the mechanism those cells are using to evade the immune system. Three, cut down on the development of new blood vessels that feed certain tumors.
Plaquenil is an example of a drug that kills fast-dividing cells. Low dose (but not high dose) Paclitaxel is an example of a
drug that enhances the natural immune response to tumors. And
Caprelsa is an example of a drug that inhibits new vessel growth. That last one can also give you a fatal heart arrhythmia, but since 44% of people on it and another cancer drug stopped progressing in their cancer, versus 1% on placebo and the other cancer drug, you bet your ass I'd take it if I needed to.
Be that as it may, we now have a target. The drug designers can get to work and try to make a molecule that hits that target and ONLY that target. Once they have that - well, let's stop there - that is no trivial task - first you have to map out the 3D structure of the target by instrument and by computer simulation, figure out what the sensitive bits are, and synthesize a molecule that can hit that and only that target while also being able to pass the through the gut when you take a pill, not have any nasty side groups that can cause other problems (known as chemotoxicity, rather than mechanistic toxicity) AND doesn't get chewed up by the liver before it even gets to the target - this can take years.
Once you have 2 or 3 compounds that fit the bill, you have to start testing them in animals. Because as good as computer sims are, we are surprised every fucking time we stick a drug in a rat. And usually the surprise is not of the "oh look, our heart drug causes boners" Viagara variety, it's usually of the "well shit, I didn't even know you could measure how much rat testicles shrink - who's the poor fucker who has to weigh the rat balls after we sacrifice the animal?"* variety.
After you've satisfied the FDA that you have done enough experiments to at least know where the likely potential problems are in humans, they let you give just one dose to college kids in need of beer money. If they don't keel over, you can work you way slowly up to a few weeks of dosing in these "healthy normals". That's Phase I.
That's normally where a small biotech goes looking for a partner. You've already spent tens to hundreds of millions by this point, and you haven't even gotten to putting it in patients with the actual disease in Phase II yet. And the really disheartening thing is - Phase II is where most drugs fail. You don't even know if you're going to have a real drug after all the money you've pissed down this hole. And even if you had the money to get all the way to Phase III and approval, you don't have the expertise. You need regulatory specialists who know what the FDA is looking for. You need veterinarians who know how to conduct the long term animal toxicity studies you now have to start (reproductive toxicology and cancer tox). You need skilled doctors who have run many clinical trials and know which sites to trust, how to set up a safety monitoring board and a thousand other details of patient safety. You need formulations chemists to make this stuff into a pill that won't choke someone - and who know how to do the environmental stability testing to determine the shelf life and get the FDA to agree on a printed shelf life for the drug. You might even need (God forbid), a controlled release formulation or some other such nonsense. And you need buy-in from the Academic medical community to publish your papers.
And even if you got through all that, for your first drug, you'll need to hire a sales and marketing team who knows their ass from a hole in the ground, or the FDA is going to Warning Letter your ass into a
smoking hole.
Most little firms such as Pharmacyclics just don't have all that expertise, and their patent clock is ticking while they dick around trying to get to proof of concept. So they need a partner.
This is where Johnson and Johnson comes in. They provide the clinical trial expertise to get from Phase IIa to launch, they provide the manufacturing capability, regulatory oversight, all the stuff I mentioned above that Pharmacyclics does not have. Pharmacyclics has some patents, some expertise at the petri dish stage, and a tiny, tiny bit a clinical expertise, just enough to get a little way into Phase II before finding a partner.
Once they have that partner, then they normally conduct a Phase IIa dose ranging study - they give a bunch of different doses to a few patients (dozens) and try to figure out what the top and bottom doses are to have the effect they want. Then they take those good doses (or dose) into some more (hundreds of) patients for 6 months or so in Phase IIb. Then they negotiate with the FDA about what they want their label to look like, and design and execute Phase III in thousands of patients for a year or more. That's assuming that it works as good as you expected (often not) and that some weird side effect didn't kill it (all too often).
Then, if nothing catastrophic showed up side effect-wise in Phase III (usually you know most of the bad stuff after Phase II, but rare side effects take more patient years of exposure to discover), they negotiate for the real label and get approval for the first disease, or "indication" in regulatory-speak. Then the sales and marketing team can get to work.
By the way, for every 30 - 40 drugs that make it out of the petri dish stage, one makes it to market. I stopped doing this kind of work over half a decade ago, after spending nearly a decade doing it. Out of nearly three dozen projects I worked on from an early stage, one made it. I'm right in line with the odds. And those are very, very expensive failures.
If the partner is smart, they pay only a little bit up front for the rights, and spread the rest of the payments out as "milestones". Say $50M up front, another $100M if the drug passes Phsae IIa, another $200M for Phase IIb and $500M for passing Phase III to launch. Then the partner takes the bulk of the profits as a reward for their risk and pays negotiated royalties on the sales back to the biotech.
That's what happened recently for ibrutinib.
And like I said, this drug is bound to cause harm in a few people. But from what I can tell, the Co$ connection extends only to the business side. The drug side went through the same FDA process - a very good process by the way - that everyone else does, and it's on the up and up. J&J would not have touched it with a 10 foot pole if that were not the case. I've never worked at J&J, but I have lots of friends who do, and they are very competent. Shit happens sometimes. If, by some ill fortune, this drug runs into a rare side effect after marketing and gets pulled or restricted, please don't blame that on the $cilons. I'll have to come over and whack you with a clue-by-four if you do.
* An actual example from my own checkered career.