The following hypothetical dialogue illustrates the elementary nature of the ‘precautionary coherence’ (PC) argument that I have detailed elsewhere. This dialogue occurs during the informed consent process when the Principal Investigator (PI) discusses with a patient the risks and potential benefits of participating in a trial. The crucial point to take away from this dialogue is that simply by taking her own interests clearly into view, a patient who has never heard of precautionary coherence can still articulate core elements of the PC principle. A subtler point that I hope will also capture your attention is how a supposed distinction between clinical trials and clinical practice, which the PI has accepted uncritically, fails to stand up to the patient’s straightforward probing.
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Patient: From what you’ve been telling me so far, Doctor, this experimental drug you’re testing sounds like something I might want to try. None of the remaining approved treatments looks very promising, but I still feel like taking action against my cancer. I appreciate your taking time to explain these “first-in-human” trials so carefully. But I’ve never been in any trial before, so I still have some questions and concerns.
PI: I’m very glad to take time to discuss this fully with you. I take informed consent very seriously. It’s one of the most important things I do. Enrolling in a phase 1 trial would be a big decision, and I want to be sure you to have all the information—and time to think about it—that you need.
Patient: I guess the first question is a very practical one: Will my insurance pay for an experimental treatment?
PI: That’s a worry a lot of potential trial participants have. But the American Society of Clinical Oncology (ASCO) has taken the position that phase 1 trials have therapeutic intent, even though they are experimental. Your insurer should pay for the routine costs connected with our trial. Any special extra costs are covered by our trial’s sponsor. That includes the cost of the drug, and the special labs we’ll do that aren’t part of routine care.
Patient: Well, that’s a relief!
PI: This is already a challenging enough decision to make, without having to deal with financial issues.
Patient: Okay, but now what about this being a “first-in-human trial”? How will you even know what dose to give me? Is it based on animals?
PI: In fact, that’s exactly the question we’re trying to answer with this trial. Animal studies unfortunately don’t tell us enough about dosing for humans. So we need studies like this one to try different doses, to see if we can strike the right balance between toxicity and hoped-for efficacy. We’re starting this trial at a pretty low dose that we think will be safe. If our guess turns out right, and participants do tolerate this starting dose well, then we’ll gradually escalate.
Patient: Oh, that sounds like what my primary care doctor did with my blood pressure medicine. So, you mean I’ll start with a low dose, and if my side effects aren’t too bad I’ll gradually go up?
PI: That’s a good observation. In a trial, though, it’s slightly different. You would start at a low dose. That’s because you’d be our third participant, and we’re still enrolling at the lowest dose in our study protocol. But what you’re alluding to is called “intra-patient dose escalation,” and our trial isn’t designed for that. According to the protocol, you would have to stay at the dose you enrolled at.
Patient: So you mean, ‘escalation’ would be for somebody else, not for me?
PI: Well, yes, I guess you could put it that way. But in our view this trial is really for all the participants. And our protocol helps keep everybody safer. Imagine if we just kept increasing participants’ doses the way I think you have in mind. Then everybody would have a 100% chance of getting an adverse effect.
Patient: I guess I’m seeing this differently. The way I’d look at it, it seems less safe how you’re doing it.
PI: How do you mean that?
Patient: Well, let’s say you eventually do escalate. That means somebody down the line will enroll, and right off the bat gets a higher dose than any human in the world has ever had before. Meanwhile, I’m sitting here doing fine at your low starting dose. Wouldn’t it be a smart precaution to let me go up a notch and have your fresh participant start at a low dose like I did?
PI: You know, in clinical practice, what you’re saying would be totally correct. Clinical trials, though, are really a totally different beast. I’ll be honest with you, there are things about these trials that I just have to leave to the statisticians. We’ve got a crack team of biostatisticians here at Prestigious Cancer Center. They’re experts in designing these dose-finding trials, and I wouldn’t want to second-guess them on the details.
Patient: I don’t know, Doctor, it doesn’t seem like a detail to me. I like ASCO’s idea that we’re trying to be therapeutic. I’m definitely not the type to volunteer to be a guinea pig. And I would start to feel like a guinea pig if I knew people coming in fresh were leapfrogging me into higher doses.
PI: I think the biostatisticians are trying to keep people safe and make sure the trial is scientifically valid.
Patient: Could I wait to enroll until you escalate and start seeing at least some side effects? I wouldn’t want to just go through the motions of a trial, and not be getting a serious dose of the drug.
PI: Hmm. Our protocol doesn’t say anything about that. But I’m not sure if it would be valid for me to call you back depending on how other patients do. That seems like something that would bias the study. But you’re asking an interesting question. And I’ll admit that, if I try to put myself in your shoes, I can definitely feel where you’re coming from as a patient. As I said, there’s no rush to make this decision. I could ask the biostatisticians in the meantime.
Patient: Well, do we work for them or do they work for us? Can we give them a call now?
PI: [Chuckles] Well, if you put it that way… [reaches for phone] But I can pretty much guess what they’ll say. They’ll ask me how I ever expect to enroll this study if I let everyone wait for somebody else to go ahead of them. But now you’ve piqued my curiosity, so here goes…” [picks up and dials]
— to be continued —