The last time I talked here at length about Andy Grove, ex-Intel CEO, I was rather hard on him, not that I imagine that I ruined his afternoon much. And in the same vein, I recently gave his name to the fallacy that runs like this: other high-tech R&D sector X is doing better than the pharmaceutical business is. Therefore the drug industry should do what those other businesses do, and things will be better. In Grove's original case, X was naturally "chip designers like Intel", and those two links above will tell you what I think of that analogy. (Hint: not too much).
But Grove has an editorial in Science with a concrete suggestion about how things could be done differently in clinical research. Specifically, he's looking at the ways that large outfits like Amazon manage their customer databases, and wonders about applying that to clinical trial management. Here's the key section:
Drug safety would continue to be ensured by the U.S. Food and Drug Administration. While safety-focused Phase I trials would continue under their jurisdiction, establishing efficacy would no longer be under their purview. Once safety is proven, patients could access the medicine in question through qualified physicians. Patients' responses to a drug would be stored in a database, along with their medical histories. Patient identity would be protected by biometric identifiers, and the database would be open to qualified medical researchers as a “commons.” The response of any patient or group of patients to a drug or treatment would be tracked and compared to those of others in the database who were treated in a different manner or not at all. These comparisons would provide insights into the factors that determine real-life efficacy: how individuals or subgroups respond to the drug. This would liberate drugs from the tyranny of the averages that characterize trial information today.
Now, that is not a crazy idea, but I think it still needs some work. The first issue that comes to mind is heterogeneity of the resulting data. One of the tricky parts of Phase II (and especially Phase III) trials is trying to make sure that all the patients, scattered as they often are across various trial sites, are really being treated and evaluated in exactly the same way. Grove's plan sort of swerves around that issue, in not-a-bug-but-a-feature style. I worry, though, that rather than getting away from his "tyranny of averages", that this might end up swamping things that could be meaningful clinical signals, losing them in a noisy pile of averaged-out errors. The easier the dosing protocols, and the more straighforward the clinical workup, the better it'll go for this method.
That leads right in to the second question: who decides which patients get tested? That's another major issue for any clinical program (and is, in fact, one of the biggest differences between Phase II and Phase III, as you open up the patient population). There are all sorts of errors to make here. On one end of the scale, you can be too restrictive, which will lead the regulatory agencies to wonder if your drug will have any benefit out in the real world (or to just approve you for the same narrow slice you tested in). If you make that error in Phase II, then you'll go on to waste your money in Phase III when your drug has to come out of the climate-controlled clinical greenhouse. But on the other end, you can ruin your chances for statistical significance by going too broad too soon. Monitoring and enforcing such things in a wide-open plan like Grove's proposal could be tough. (But that may not be what he has in mind. From the sound of it, wide-open is the key part of the whole thing, and as long as a complete medical history and record is kept of each patient, then let a thousand flowers bloom).
A few other questions: what, under these conditions, constitutes an endpoint for a trial? That is, when do you say "Great! Enough good data!" and go to the FDA for approval? On the other side, when do you decide that you've seen enough because things aren't working - how would a drug drop out of this process? And how would drugs be made available for the whole process, anyway? Wouldn't this favor the big companies even more, since they'd be able to distribute their clinical candidates to a wider population? (And wouldn't there be even more opportunities for unethical behavior, in trying to crowd out competitor compounds in some manner?)
Even after all those objections, I can still see some merit in this idea. But the details of it, which slide by very quickly in Grove's article, are the real problems. Aren't they always?