The phase 0 study is not for all drugs. The approach is most appropriate "if there's a very straight yes or no answer," Kummar says. In other words, if confirming that a drug does what it was designed to do offers enough evidence to proceed to later phases—this isn't always the case, depending on the drug—then a phase 0 study is a logical first human trial. Phase 0 is also excellent for testing new delivery methods of existing drugs. Specifically, many intravenous drugs are now being converted to pills and other oral formulations, but swallowed compounds may affect the body differently from injected ones, a phenomenon easily evaluated in a phase 0 study.
The approach isn't perfect: if a drug fights disease in ways that researchers don't anticipate, a phase 0 trial can prove it ineffective even though it is actually beneficial. Nexavar, a recently approved drug, is a good example. It offers significant advantages in the treatment of liver and kidney cancers. Researchers initially believed that Nexavar worked by inhibiting an enzyme called B-raf. But the compound probably exerts its anticancer powers through other means. A phase 0 trial might have shelved this drug instead of getting it to the bedside of suffering patients.
And what's a pharmaceutical industry story without a little skullduggery? Drug companies, it turns out, may shun phase 0 trials precisely because they can be so effective. "People don't [always] want to find out if the drug is not working," Kummar says. It's not always advantageous to find out that your experimental agent doesn't work. A biotech company with a few drugs in the pipeline can keep investors interested with a "promising" new drug—and it's not that hard to show that a drug is promising—letting the company stay afloat for long enough to develop the next compound in its pipeline. Similarly, academic investigators in need of grant-earning publications would rather publish positive studies than negative ones.
But that's where the true value of the phase 0 trial lies: in halting, early on, the development of drugs that aren't any better than what's already available. The problem with the traditional phase I to III "critical path," as it's called, is that drugs often make it to phase II only to be proven ineffective, and sometimes even all the way to phase III. In fact, a new anticancer agent just failed a phase III study. "It turns out that it doesn't do what the company thought it did," says James Doroshow, of the National Cancer Institute, who declined to name the compound (the news will be public in a couple of months).
Still, the phase 0 trial probably won't bring down the commercial cost of drugs: the final price tag more closely reflects what the market will bear than the actual dollars spent on R & D. But the money saved could instead be directed elsewhere—toward, say, a dozen phase 0 studies instead of a single phase II. These trials would increase the odds of finding truly beneficial new compounds, potentially speed up the process, and spare a lot of patients dashed hopes. They might not lead to the next great cancer drug immediately, but they're a step in the right direction.
Image: Lyle Stafford/Reuters