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Tuesday, February 12, 2013

End of Phase 2

Phase 3 drug development may be the expected climax of a long story, but phase 2 is where the seeds are sown and the ending is set in motion. By the time phase 2 is half way through, one would have a pretty good idea about whether the drug would theoretically work. In other word, the concept is proved or disproved.

Yet, theory and reality often slip away from each other like two pieces of iceberg in the middle of an undercurrent. Any tiny or potential glitch --- a seemingly insignificant side effect, or a slightly messy or low receptor binding profile, for example --- could be blown up exponentially in phase 3 clinical trials, when many more subjects present many more real-life variations on the controlled laboratory/clinical environment. Some may have other clinical or subclinical conditions or genetic predispositions that negate the efficacy of the drug. Some may throw away the study drug and report they have complied with all instructions. Some may be hypochondriac and report every little discomfort as a side effect. Welcome to the real world.

The crux at the end of phase 2 is whether to abandon a drug or move it into phase 3. In today's pharmaceutical environment, the psychological incentive is overwhelmingly biased toward moving it along rather than letting it go. Look, it is easier to throw out a molecule when you've only spent a million dollars in animal studies or tens of millions in phase 1 trials. But when you've already sunk fifty million into the molecule, your psychological scale is inevitably tipped to the side of success. Of course, if the drug is clearly a dud in phase 2, the choice is easy if painful. Many times, however, the choice is just not clear. The drug might look good on a couple of efficacy endpoints but fail in another endpoint. Or the overall efficacy is no better than placebo, but it beats placebo in a couple of biomarkers. To phase 3, or not to phase 3, that is the question.

I have heard one theory that is unproven but rings true. In most companies, the same team fosters a molecule from start to finish. They feel psychologically invested in the drug after years of development and tons of their sweat and tears. By the end of phase 2, they see the drug less as a molecule, but more like a baby --- worse, their own baby! How can they resist throwing another hundred million dollars (often more) into phase 3 trials to see if the baby would turn out just fine?

If you do the math though, a few hundred million dollars could have run a few more molecules through phase 1 and phase 2 and potentially home in on one that works unequivocally. On the other hand, this could mean a delay in the rush-to-the-market arms race. Again, the mind is biased in favor of pushing into phase 3 despite all the doubts and questions.

To abandon a possible dud by the end of phase 2 makes everyone look bad. For a large company, it's an ugly truth that would send Wall Street analysts into a selling frenzy. For a small company, it could mean survival or bankruptcy. Thus all the more reason to put on a happy face and throw more good money after bad. 

Perhaps this is why we are seeing so many phase 3 flops lately --- the financial stakes are higher, the scrutiny is tighter, and the hypes more unrealistic. The chips are stacked against objective, ruthless decisions.


talich said...

Phase 2 一般只是剂量研究吧,没有真正的 case-control study。感觉到这阶段,还是很不靠谱的。


Jun said...

不,Phase 2 已经是 proof of concept 的阶段了,efficacy, safety, dose-finding 都要研究,只是 sample size 小。Phase 2 特别关键,也特别容易把公司引入 phase 3 的泥潭。

Talich 同学看样子是半个同行,给我发个 email address 学术联络一下?在微博里短信给我也行。

talich said...

对,efficacy,safety,dose-finding 是肯定要的。

不过好像 phase 2 是不要求严格意义上的 case-control 的。就是说证明它有效,但不一定要跟其他治疗做双盲比对这种。

比如前两天的看 Rosenberg 的一个黑色素瘤的 phase 2,就是这种。

Jun said...

癌症药的 clinical trials 标准跟其他病有点不同,phase 1 在病人而不是健康人身上试验安全, phase 2 大多是 open label, phase 3 也基本不用 placebo control, 因为给癌症病人 placebo 是不道德的。癌症 clinical trials 的人数常常比其他药的人数少,而且 risk/benefit 的平衡也松很多 --- 毕竟是 life threatening disease。

撇开癌症不算,phase 2 要不要 randomized, placebo-controlled, double-blind 设计一般因病而异,主观因素大 bias 明显的病症还是需要全套的设计,否则疗效更没法信了。

talich said...

癌症是肯定不用 placebo 的。好像心脏病这样的也是一个逻辑。不过我老板很不以为然,觉得很多抗癌药比 placebo 还差劲。heihei

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