So is this the attitude we're up against? Here's a thread on Slashdot on the clinical trial disclosure issue - titled, I note in light of yesterday's post, "Medical Journals Fight Burying of Inconvenient Research". My favorite verb again! The comments range from the insightful to the insipid (for another good reaction to the clinical trial controversy, go here.)
A comment to the original Slashdot item disparages the idea that NIH is the immediate source of all drugs, and recommends reading my site, both of which actions I appreciate. But the first response to that was:
"No, (NIH-funded labs) just do the basic research that results in the drug leads. The companies then do the expensive but scientifically easy trials and rake in all the money (and now it seems, the credit as well)."
Wrong as can be, and in several directions at once. In a comment below, blogger Sebastian Holsclaw urges that we take this kind of talk seriously because it's more widespread than we think. I'm afraid that he might be right. The problem is that many people don't seem to understand what it is that people like me do for a living. I think that there must be plenty who don't even grasp how science works in general. Allow me to go on for a while to explain the process - I'd appreciate any help readers can provide in herding the sceptics over to read it.
Try this: If Lab C discovers that the DooDah kinase (a name I whose actual use I expect any day now) is important in the cell cycle, and Lab D then profiles its over-expression in various cancer cell lines, you can expect that drug companies will take a look at it as a target. Now, the first thing we'll do is try to replicate some of the data to see if we believe it. I hope that I'm not going to shock anyone by noting that not all of these literature reports pan out.
But let's assume that they do this time, making DooDah a possible cancer target. What then? If we decide that the heavy lifting has been done by the NIH-funded labs C and D, then what do we have so far? We have a couple of papers in the Journal of Biological Chemistry (or, if the authors are really lucky, Cell) that, put together, say that DooDah kinase is a possible cancer target. How many terminally ill patients will be helped by this, would you say? Perhaps they can read about these interesting in vitro results on their deathbeds?
What will happen from this point? Labs C or D may go on to try to see what else the kinase interacts with and how it might be regulated. What they will not do is try to provide a drug lead, by which I mean a lead compound, a chemical starting point for something that might one day be a drug. That's not the business these labs are in. They're not equipped to do it and they don't know how.
(Note added after original post): This is where the drug industry comes in. We will try to find such a lead and see if we can turn it into a drug. If you believe that all of what follows still belongs to the NIH because they funded the original work on the kinase, then ask yourself this: who funded the work that led to the tools that Labs C and D used? What about Lab B, who refined the way to look at the tumor cell lines for kinase activity and expression? Or Lab A, the folks that discovered DooDah kinase in the first place twenty-five years ago, but didn't know what it could possibly be doing? These things end up scattered across countries and companies. And all of these built on still earlier work, as all the work that comes after what I describe will build on it in turn. That's science, and it's all connected.
Here in a drug company, we will express the kinase protein - and likely as not we'll have to figure out on our own how to produce active enzyme in a reasonably pure form - and we'll screen it against millions of our own compounds in our files. We'll develop the assay for doing that, and as you can imagine, it's usually quite different than what you'd do by hand on the benchtop. Then we'll evaluate the chemical structures that seemed to inhibit the kinase and see what we can make of them.
Sometimes nothing hits. Sometimes a host of unrelated garbage hits. For kinases, these days, these usually aren't the case - owing to medicinal chemistry breakthroughs achieved by various drug companies, let me add. So if we get some usable chemical matter, then I and my fellow med-chemists take over, modifying the initial lead to make it more potent, to increase its blood levels and plasma half-life when dosed in animal models, to optimize its clearance (metabolism by the liver, etc.), and make it selective for only the target (or targets) we want it to hit. Often there are toxic effects for reasons we don't understand, so we have to feel our way out of those with new structures, while preserving all the other good qualities. It would help a great deal if the compounds exist in a form that's suitable for making into a tablet, and if they're stable to heat, air, and light. They need to be something that can be produced by the ton, if need be. And at the same time, these all have to be structures that no one else has ever described in the history of organic chemistry. To put it very delicately, not all of these goals are necessarily compatible.
I would love to be told how any of this comes from the NIH.
Now the real work begins. If we manage to produce a compound that does everything we want, which is something we only can be sure of after trying it in every model of the disease that you trust, then we put it into two-week toxicity testing in animals. Then we test in more (and larger) animals. Then we dose them for about three months. Large whopping batchs of the compound have to be prepared for all this, and every one of them has to be exactly the same, which is no small feat. If we still haven't found toxicity problems, which is a decision based on gross observations, blood chemistry, and careful microscopic examination of every tissue we can think of, then the compound gets considered for human trials. We're a year or two past the time we've picked the compound by now, depending on how difficult the synthesis was and how tricky the animal work turned out to be. No sign of the NIH.
The regulatory filing for an Investigational New Drug needs to be seen to be appreciated. It's nothing compared to the final filing (NDA) for approval to market (we're still years and years away from that at this point), but it's substantial. The clinical trials start, cautiously, in normal volunteers at low doses, just to see if the blood levels of the compound are what we think, and to make sure that there's no crazy effect that only shows up in humans. Then we move up in dose, bit by bit, hoping that nothing really bad happens. If we make it through that, then it's time to spend some real time and money in Phase II.
Sick patients now take the drug, in small groups at first, then larger ones. Designing a study like this is not easy, because you want to be damn sure that you're going to be able to answer the question you set out to. (And you'd better be asking the right question, too!) Rounding up the patients isn't trivial, either - at the moment, for example, there are not enough breast cancer patients in the entire country to fill out all the clinical trials for the cancer drugs in development to treat it. Phase II goes on for years.
If we make it through that, then we go on to Phase III: much, much larger trials under much more real-world conditions (different kinds of patients who may be undergoing other therapy, etc.) The amount of money spent here outclasses everything that came before. You can lose a few years here and never feel them go by - the money that you're spending, though, you can feel. And then, finally, there's regulatory approval and its truckload of paperwork and months/years of further wrangling and waiting. The NIH does not assist us here, either.
None of this is the province of academic labs. None of it is easy, none of it is obvious, none of it is trivial, and not one bit of it comes cheap. We're spending our own money on the whole thing, betting that we can make it through. And if the idea doesn't work? If the drug dies in Phase II, or, God help us all, in Phase III? What do we do? We eat the expense, is what we do. That's our cost of doing business. We do not bill the NIH for our time.
And then we go do it again.