I want to tell you about the most exciting discovery I’ve made in 2+ years of research on dose individualization methods for phase 1 cancer trials. This discovery has nothing to do with any of the technical problems I’ve confronted and solved along the way. It involves no gigantic equation, no table of simulations results, and no colorful plot. Rather, it’s a discovery about sources of power to innovate in drug development.

In general, how would you describe the balance of power between Big Pharma and the individual patient? The question seems ludicrous—maybe even offensive—in light of ongoing scandals with price-hikes and shortages for critical drugs. But in the special area of trial methodology, I’ve got a real surprise for you…

One result from my DTAT research has been a clear demonstration that 1-size-fits-all dose finding in phase 1 cancer trials can cut the value of a drug in half, or even drop it to zero by setting the drug up for failure in phase 2 or 3. Although this economic argument has never been made quite so explicit and rigorous, I am certain the underlying principle comes as no surprise to anyone. (I note hardly anyone bats an eye when I detail the math.) This implies that Big Pharma has stuck with 1-size-fits-all dose finding for decades, in willful ignorance of huge financial costs it imposes on their shareholders. How does a supposedly powerful corporate interest fail to innovate its way out of such a costly hole?

As I’ve shopped my DTAT briefing around for the past year—through a dozen audiences with Pharma and the CROs they hire to run their trials—I’ve formed a theory about Pharma’s helplessness to innovate in this area. At a technical level, my talks usually spark such enthusiastic discussions that I now tend to see Pharma as swarming with methodologists hungry to innovate. (One exceptionally brainy audience recently saw straight through to DTAT’s current conceptual boundaries and urged it on into new territory!) But when discussions shift to the level of practical action, the mood sinks. Those innovative voices go quiet. Executives hurry to offer excuses for paralysis. The air fills with what a sharp-witted methodologist colleague of mine calls “dissent by proxy,” which he pointedly defines as appealing to the objections of somebody who’s not in the room. When he first taught me this delightful phrase, I considered it a penetrating dissection of a bad rhetorical maneuver, but nothing more. Yet over time, I’ve come to appreciate it as a much richer idea, one that yields a full diagnosis for why serious methodologic innovation proves nearly impossible to achieve from inside Pharma’s corporate confines.

I now think that call it what you may, you cannot simply dismiss dissent-by-proxy as some cowardly rhetorical maneuver. Not in the realm of clinical trial methodology, anyway. In this context, dissent-by-proxy is a factually correct argument! Trial methodology is inextricably entangled with regulatory risk, and Pharma has acquired a pathological sensitivity to this specific type of risk far out of proportion to the manifold other risks inherent in drug development. Never mind that this sensitivity seems also badly out of step with our new, more forward-thinking FDA. This sensitivity remains a fact of life, imprinted upon the corporate culture of Pharma. Consequently, that ‘proxy’ outside the room is no mere bogeyman. It’s a cultural norm: What if you stick your neck out as a methodologist to design a truly innovative trial, and that trial happens to roll snake eyes on the drug-discovery dice? Your methodologic innovation becomes Scapegoat One! The career-risk calculus for the Big Pharma methodologist effectively forbids genuine innovation.

But, what of patients and their power? How does the lone patient have any power at all, in a setting where even powerful corporations can’t make methodological advances that are plainly in their shareholders’ interest?

When the supposedly weak discover an unexpected source of power, so often they find it in a logical principle. The Montgomery Bus Boycott, for example, deployed the inexorable logic of supply-and-demand to deal a punishing blow to that city’s transit system. (Some even argue that nonviolence, in general, possesses an underlying ‘strategic logic’.) Consider also the unforgettable metaphor of Dr. Seuss’s Yertle the Turtle. Why can’t we grown-ups forget this children’s book? Because it perfectly maps the abstract logic of Mack’s power (and his suffering) onto our concrete experience of gravity. Mack’s position at the very base of King Yertle’s ‘throne’ gave him at once the greatest incentive and the most power to topple it.

For phase 1 trial participants, an analogous logical power derives from the precautionary coherence (PC) principle described here. The logic works like so:

• A patient who is sufficiently knowledgeable and self-actualized will ask certain questions and seek certain assurances when being consented into a phase 1 trial.
• If that trial has a non-PC design, then this informed consent conversation must either degenerate into a take-it-or-leave-it proposition fundamentally distasteful to both parties or else yield to a negotiation that unravels the design.

Someday soon, we’ll see a ‘Rosa Parks moment’ in phase 1 trials: A knowledgeable patient articulates the PC principle during informed consent and refuses to budge. A befuddled clinical investigator scrambles for excuses but finds none. Word gets out and travels up the chain of command. A dose-escalation design begins to unravel… into a dose-titration design. We’ll learn from this how one patient holds more power over phase 1 trial design than an entire industry.