The Uncomfortable Reality of Clinical Trials
How do we make clinical trials make sense to participants and study sponsors?
Welcome to The Frontier Psychiatrists newsletter—a daily enough health-themed publication. Today, an essay inspired by the work of Dan Karlin, M.D. He’s a friend, mentor, CMO at MindMed. He’s a scholar who also cares deeply about the patients he serves as a clinician and the research subjects who pave the way to novel treatments.
When there is a discomforting concept, we continually rename it. That's how you know that our relationship with participants as researchers is discomforting. The linguists came to the same conclusion: When a discomforting concept exists in the world, you can almost always find it using this “one weird trick.”
The name for it keeps changing. We used to have homeless people. Then, they became unhoused. Now they're undomiciled.
That sounds way better.
However, they're still sleeping on the street. We didn't fix it. We just renamed it, so it felt a little better. To us, people are most likely not forced to spend any time sleeping on that— or any—street, it’s less awkward. If you think about many of our discomforting concepts, the shifting names identify them, while those suffering don’t have time for such foolishness.
We can't quite figure out what to call the people we're doing experiments on. Something uncomfortable? We can’t help but notice that we are not incentive-aligned with the people who enrolled in our studies. Participants. Subjects. The list goes on.
What do we do to try to fix that? We try to align those incentives, lower the burden to participate, ensure people are compensated for their time, and ensure that they're incentivized to stay in the study. Hence, their data ultimately end up being useful for the purpose for which they enrolled in the study in the first place—to bring new treatments to others suffering.
We randomize them; we have to, right?
Among those designing trials for novel therapies, we are now including extension phases in trials. But we don't randomize that part of the trial. Thus, people can get what they want. There's the trade-off. This is one way we align incentives. During the randomized portion, we get more useful, higher-quality data that speaks to causality. During the extension phase, when people can get open-label treatment, we get lower-quality data. But we're giving someone treatment, and we can learn from it. When you look at clinical trials and the ecosystem that supports them, our goal setting always needs to be on the lookout for tension between us—the investigators—and our subjects. We must bring those parties into close alignment, recognizing that they can never be fully aligned.
Tactical compromises could get us most of the way there. One way we do this is two-to-one randomization. Another might be the open-label extensions mentioned above. Or cross-over designs, so everyone gets active treatment sometimes?
All that is for naught if we ignore the most crucial question: how do we build trust? Well, you're asking somebody to take a risk. We want our subjects to be invested in the study’s accuracy. The drug may or may not work. The adverse events will be suffered by the study subjects, not the researchers.
At some point, they may or may not know what they're on. We historically didn't disclose this. We never gave subjects the data. It was like it disappeared into a black hole. Among my colleagues, we generally found an upfront investment in time, and education pays dividends. This is in terms of both ethics and dispassionate science. We need to relish talking to a potential subject about this trade-off— here's what it takes. Without what we learned from your experience, we can't know if this therapeutic works. Without your honest and thorough reporting, we can't prepare millions of people for the risks they will face.
I've seen people examine an informed consent form—it’s incomprehensible. They're legal documents. This is not informed consent in how people conceptualize its platonic ideal. Lawyers write these. They do this because they're designed to avoid liability. But if you read them? It would take me a week to go through informed consent and figure out what I'm actually being asked to consent to.
Do I really understand the risks? Do I really understand what the study subject understands? One of the things that we can do is be more understandable. But one of the things that I found effective? It is buying investigator time or study coordinator time early to have those conversations with potential subjects. If we pay for it, they will prioritize these conversations, like any other line item in a budget.
Pay them to help subjects understand why. Now, you have your study subjects as a committed partner in a study. This is as opposed to somebody who's thinking: what's the minimum commitment I have to make? Because absent this shared understanding, study subjects and investigators will not share similar enough goals. There's a fundamental difference in how we view people who decide to come in to our trials. To me, they are participants or subjects in an experiment.
A critic of this approach might say: “I don't resort to any payment! We don’t want to do this or that! What about something or other?” That “a critic” has been in the industry a long time, surely their concerns are meritorious?
But our study subjects are humans in an experiment! Let's not kid each other. They're part of it. And if we knew the answer to the study? We would be doing something other than the study. We have to be transparent with our subjects, and part of what we're trying to figure out is whether this intervention even works.
When I've had those discussions with families or subjects, they understand that they are an integral part of a solution to a serious question. Trust is built there. Subjects must understand, “I am part of the solution to suffering.” We invite research subjects to help us answer questions together.
It is a different kind of social contract. Sometimes, we aren't clear enough that when you come and see an investigator, it is not the same as coming to see a doctor. The rules are different, and we need to let people participate in a different way and answer questions differently. There is a real place for signposting and being clear that this study exists to answer an important question. This is not trivial research. We aren’t going through the motions for insurance authorization—we don’t know the answer unless our subjects tell us the truth in the course of the experiment.
If I look at oncology, there is an altruistic motive for participating. I think altruism is also present in psychiatry, but we do not tap into that enough. People are participating in trials for others, not just for themselves. We should be helping them think about what this might be doing for their relatives, loved ones, and other humans, too. This isn't what happens when you go to the doctor because you're sick. In that context, you're choosing to care for yourself. It's private; no one else should know. In a clinical trial, however, part of what makes your participation meaningful is that everyone will know what happened to you in aggregate. Research subjects are looking for relief for themselves, with the wish to take a calculated risk to save somebody else's heartache. This is a risk-taking boldness that comes with risk assumed.
When I've taken care of terminally ill patients, the one thing routinely I would hear is, “I know I'm going to die; please don't abandon me. I don't want to die alone.”
Clinical trial subjects might have very similar fears. Let’s not abandon them. Treat them like colleagues. Because… they are.
Your author, Owen Muir, at the age of 20, volunteered as a research subject at Columbia University. He got a lumbar puncture from J. John Mann. He encouraged his entire family to enroll in a large NIMH family study. It was that experiences as a subject that led him to return, again and again, to a role as an investigator.
Thanks for reading.
So many clinical trials are controlled by specific academic medical centers limiting the opportunity for patients who have failed their disease state standard of care the opportunity to participate in a legitimate trial. Most of the trials nationally go unfilled or under-filled. Further, since there’s not a legitimate marketplace for clinical trials (legitimately signaling demand for specific conditions and rare diseases back to innovators of potential solutions); the system is both inefficient and fragmented to say nothing of the quality of the care delivery system that manages the trial(s). Following the movement toward payment reform/care transformation; it would be nice to emancipate clinical trials from specific academic medical centers thereby giving value oriented care delivery systems the opportunity to access ANY clinical trial on behalf of their patient……allowing them to manage the patient and the trial. Solves many of the social determinant issues and gives the patient better opportunity for successful outcomes while maintaining a relationship with a provider or team that they trust.