There’s one good thing that I can say for the current environment in the drug industry. I’ve had to stare out the window for a while to think of it, but here goes: necessity is still the mother of invention. And that means that we must be headed for some inventions pretty soon, because the need is most certainly there.

Herbert Stein, the 1970s economist, used to sum up disturbing trend lines in the data by saying, “If something cannot go on forever, it will stop.” He wasn’t necessarily being optimistic, of course: the numbers might be telling you that some calamity is on the way, and by gosh, so one is. Stock market bubbles are a good example of that, not that you can get everyone to agree while one is going on. But the rest of the time, what that saying means is that conditions get altered.

An example might be the wilder-eyed “peak oil” people. They look at the line showing proven oil reserves, and say, “Ah-hah! Here’s where the total starts going down, and that’s where the wheels start coming off!” But what they’re really predicting is the end of cheap, easy oil. If you’re willing to go to the trouble of extracting it from tar sands or shale, there’s a lot more oil out there than you’d think. And in the same way, if you’re willing to retool to use natural gas as a fuel or feedstock, well, there’s a lot more of that than people used to think, too. What they’re also predicting is that people won’t alter their behavior in response to powerful incentives, which has always seemed to me like an odd bet.

That’s what we’re up against in this industry. Our traditional methods of discovering and developing drugs are yielding an unsustainable number of dry holes, to stick with the oil-drilling metaphors. If you draw the line heading up (costs) and the line heading down, or at best sideways (drug approvals), you think, “This can’t go on.” And Herbert Stein would tell you that you’re right, it won’t. But since people are still getting sick, and since there’s still plenty of money to be made by treating them, I have to think that we’ll adapt to find some way to keep going.

“Such as?” is the natural response to a statement like that, so I owe a few examples in return. I can think of several. For one, I think we’re going to have to rethink the way we approach clinical trials. I think we’re going to see – or more properly, we’re going to have to see – fewer good ol’ gigantic, full-rigged, na�ve-patient Phase III extravaganzas. Our step-by-step method makes a lot of sense, but – given our shaky knowledge of a lot of important biology – it also sets us up for some monstrous whopping failures in the late stages, after all the money’s been spent. There are so many disease indications that can’t even be reliably tested until we get to Phase III under our current protocols, that the risk – both financial and scientific – is just getting too big to bear. I believe that we’re going to have to move to more adaptive trial designs, where Phase II and Phase III blend into each other, with patients being enrolled continuously.

Here’s a small-scale example of what I mean. Remember TeGenero? That was the little immunology company in Germany that tried out their T-cell stimulating idea in six volunteers in 2006, and nearly killed them. Every one of them collapsed, went into a terrible cytokine-storm immune response, and were rushed to extended stays in intensive care. One of the problems here was that clearly, they (and we) didn’t understand as much about messing around with human T-cell therapies as they thought. Another problem was that they approached this frontier all at once, dosing the six subjects within minutes of each other. If they’d waited a half-hour between each patient, they’d have never gotten past the first one. (As it was, they got to watch them go down one by one, unable to do a thing about it).

That, unfortunately, is a model for how we do a lot of clinical trials – not from a safety standpoint, but from a mechanism-of-disease one. There’s no way to see if you’re making headway against something like, say, Alzheimer’s until you get to Phase III, so we spend a huge amount of money working our way up to that point, then we round up a huge number of people, dose them more or less all at once, and cross our fingers. Does that characterization sound harsh? Well, look at Eli Lilly’s recent Phase III failure with their gamma-secretase inhibitor. I mean, the etiology of Alzheimer’s is still very much a subject of debate. The usefulness of a gamma-secretase inhibitor is, too, and there’s always that chance that some particular drug won’t work right even if it’s targeting the right mechanism. That adds up to a lot of risk, and Lilly ended up walking right off a cliff while trying to deal with it using our current tools. There has to be a better way.

Moving back from the clinic, there are a lot of unconventional approaches that we’re going to have to break out. These are our equivalents of oil shales and tar sands, and we’re going to need all of these that we can get while we keep working on our equivalents of fusion reactors and orbiting solar power. Some examples? Try covalent inhibitors, which have long been given the fishy glance in drug discovery. But if we can make selective compounds with reactive groups that aren’t red-hot – and if we can test them for efficacy and toxicity without going bankrupt – there could be some useful things in there. Another example are the various schemes for stabilized proteins and peptides, hybrids between biologics and conventional synthetic drugs. There’s a lot we don’t know about these things, but there’s a lot of promise there, too. Again, we just need to be able to test these things out as quickly and definitively as possible, since there are surely many ideas here – especially at first – that aren’t going to work out quite the way we plan.

We can keep going. How about all the unusual drug delivery platforms? Nanoparticles (of which there are many), conjugates to active-transport molecules, exotic prodrugs: if we can extend the boundaries of what kinds of drug substances are usable, our success rates might start to nose upwards again. Speaking as a medicinal chemist, I wouldn’t mind if the range of acceptable molecular weights moved up a bit, or if the range of properties for a CNS-active drug widened. To be honest, these technologies are things that we probably wouldn’t bother messing around with if we had enough conventional drugs to occupy everyone. At the very least, the pace of research wouldn’t be what it is now (and will be).

When you think about it, the old saying doesn’t quite go far enough. It’s not necessity but desperation that is the real mother of invention. And if that’s what it takes, well, we’ve got plenty of that to go around. Let’s see what it can bring us.

In the Pipeline � A Whistleblowing Record

The former GSK employee who went to the FDA about quality control problems in their manufacturing has been awarded $96 million dollars for her work (it’s calculated as a share of the fine against the company). This breaks all previous records – and you know, I think that’s a good thing.

I’ve written about this sort of thing before, and I continue to think that this is a good law. It takes a tremendous amount of nerve to put your own livelihood at stake to report something that’s going wrong (and isn’t being fixed). The incentives need to be there. If we were a perfectly altruistic species, any of us would have no problem sacrificing ourselves immediately for the good of the whole. But the very fact that there’s such bad conduct to take the risk of reporting on tells you that we’re not that sort of species at all. Here’s an excerpt from the UK Guardian’s article about it (http://bit.ly/aFauKJ):

The case centred on a factory in Cidra, Puerto Rico, where GSK made a range of products including an antibiotic ointment for babies, and drugs to treat nausea, depression and diabetes. In August 2002, Eckard, a global quality assurance manager, led a team sent to the plant to investigate manufacturing violations that had been identified by the U.S. Federal Drugs Administration (FDA). Eckard lost her job nine months later after warning that the problems ran deeper than the FDA realised.

Eckard’s lawyers, Getnick & Getnick, said she was made redundant against her will in May 2003 after repeatedly complaining to GSK’s management that some drugs made at Cidra were being produced in a non-sterile environment, that the factory’s water system was contaminated with micro-organisms, and that other medicines were being made in the wrong doses . . .

. . . Eckard tried to alert GSK’s management to the situation in Cidra even after she left the company. According to the lawsuit brought by Eckard, she tried to call GSK’s chief executive JP Garnier in July 2003, but he declined to speak to her. She took her concerns to the FDA in August 2003 after concluding that GSK’s compliance department lacked the authority to address her concerns.

I’m not enough of a libertarian to think that the market will take care of all such behavior without an extra possibility of punishment backing it up. I think that we really do need regulatory authorities (although we can argue the details after that statement!), in the same way that we really do need police forces. Both of those groups can (and do) abuse their authority at times, but both of them also provide a much-needed function, human nature being what it is.

And the nature of big organizations being what it is, too. “Never explain by malice what can be explained by stupidity” is a pretty good rule, and in a large company, you can add inertia, backside-covering, careerism, and deciding that a given mess is someone else’s problem. The bigger a company, the more chances there are for these things to happen. Perhaps the possibility of a $750 million fine will help to concentrate attention in such cases – and if not, well, how about a billion? Try for two?

from http://pipeline.corante.com/ on 11/29/10Copyright Derek Lowe, 2010

Derek B. Lowe has been employed since 1989 in pharmaceutical drug discovery in several therapeutic areas. His blog, In the Pipeline, is located at http://www.corante.com/pipeline and is an awfully good read. He can be reached at [email protected].