Zero justification

If you ask people why drugs typically fail in the clinic, you’ll usually hear something about toxicity. Of course that’s a big problem, but there’s another one which is just as large, and arguably even more disturbing: efficacy. That’s right - a substantial number of investigational drugs fail because they just don’t work. The disturbing part is, of course, that no one takes a drug into human clinical trials without a well-founded belief in their mechanism of action, which shows you just how much we have to learn about what we’re doing (and how expensive the lessons are). 

In an attempt to deal with this problem, the FDA has issued guidelines in the US for what are being called ’Phase Zero’ trials. These are designed to involve a minimum number of patients who receive a sub-therapeutic dose of a new drug candidate. The whole purpose is to see if the drug is actually hitting its intended target. There’s also a chance to get a first read on whether the compound shows the expected distribution and blood levels, the traditional role of a Phase I trial. 

These trials are necessarily run before safety has been thoroughly established in humans. And if Phase Zero trials are run in patients with the disease under study, which they’ll usually need to be, the subjects will have no real chance to benefit from the trial. The counterargument is that compounds with little hope of efficacy will be prevented from making it into later studies, which is surely a net ethical gain. Still, it’s no surprise that the idea has been first rolled out for cancer therapies, where the unmet medical need makes many things easier to justify. 

Moving targets 

Whether Phase Zero catches on depends on several questions without obvious answers. For one thing, many compounds don’t have a clear mechanistic readout in humans. A lot of money is going into searching for useful biomarkers, far more than would be necessary if the job were an easy one. A test of the activity of a drug’s protein target before and after dosing is probably the best marker available, but that’s not always possible from blood or biopsy samples. 

Then there are the compounds that hit multiple targets. The oncology field has plenty of those, particularly kinase inhibitors, but we have little idea of which targets are the most important. To complicate things further, the most valuable component of a multiple-target cancer drug’s activity might vary between different phases of therapy, and is surely different for different tumor types. At the other end of the scale, not all drugs have a defined mechanism at all by the time they enter clinical trials, which could rule a Phase Zero trial out completely. 

The final complication is the largest one: what of the drugs that are well-aimed, but at targets that turn out not to work? A worrisome number of efficacy failures are in just this category. Phase Zero trials in such cases could be a waste of effort, but (naturally enough) we don’t know a priori which cases these are. As more of these trials are run, the size of this problem may become apparent. 

Failure means success 

How many will be run, though? Clearly, there are a limited number of suitable candidates. And there’s always the chance that the idea might not catch on with many clinical development organisations, which (understandably) are not always filled with people who are in a mood to try something completely different. A conspicuous success would do a lot for the idea, of course. But keep in mind that the idea is to kill off compounds before spending more time and money on them. 

What costume would success wear, then? If the target appears to be hit, that’s fine as far as it goes. But that means that press releases about successful Phase Zero trials aren’t going to be worth very much, at least until the compounds progress to Phase II and efficacy testing. Even if they fail there, that says more about the choice of the early marker (or the target) than it says about the trial design. But if you see compounds being abandoned even before Phase I, that means that Phase Zero trials are truly being taken seriously. And if we don’t see such decisions, we should ask whether it’s worth running them at all. 

Derek Lowe is a medicinal chemist working in preclinical drug discovery in the US