I recently attended a patient summit where all stakeholders grappled with the ‘gamble’ of placebo in trials in critical situations. My mind and heart were stirred as I learned some of what patients with PBC experience in their clinical trial journey. I wrote the following LinkedIn post the next day to try to make others aware of how patients are caught in the middle of the RCT dilemma: “Is ‘good science’ always good ethics?”

Consider this general scenario, often a point of tension in RCT ethics: You’ve just received devastating news; a chronic, life-threatening diagnosis. Your prognosis? Maybe three years. Hope arrives via a clinical trial, but it’s an RCT. You face a significant chance of receiving a placebo. You’re asked to “gamble” precious time for “good science.”

Does this align with the Hippocratic Oath? What’s wrong with this picture? This hypothetical hit home learning about the context for Primary Biliary Cholangitis (PBC). I was fascinated, and frankly concerned, to understand that the use of placebo controls in clinical trials is the norm for this patient group, including in later stages or when options are limited.

I find myself asking why this specific standard persists for PBC. Crucially, this raises a direct question for our regulatory bodies (like EMA, FDA, MHRA): What is the regulatory perspective that permits, or perhaps encourages, this approach for PBC, potentially creating disparities compared to how other conditions might be treated in trials? How do current guidelines ensure the balance between placebo data needs and the ethical considerations for patients with progressive diseases like PBC? How do we ensure this approach is ethically sound and transparently explained to PBC patients weighing their options during a vulnerable time?

Honestly, hearing this, my gut reaction is: This can’t be right! Are we truly balancing scientific need and the immediate well-being of individual patients effectively here? This specific example underscores the broader challenge: How do we reconcile rigorous evidence needs with our ethical obligations? Are alternative trial designs underutilized, especially in progressive conditions? Where does true informed consent lie in these high-stakes scenarios?

And why PBC? How many other conditions does this impact? How many other patients? Is this more common than being related to just this condition? The reality is: yes, there are a host of other illnesses, more patients who experience this on a daily basis. Something has to be done on a broader scale.

The Weight of Hope in Clinical Trials

We understand that participating in a clinical trial is not something that patients do halfheartedly or take lightly. Many patients enrol seeking a cure for a serious condition. Others just hope to find a better treatment option, a better alternative to the options they’ve been given. But no matter the reason behind your participation, you have chosen this path with hope and courage, with many hours of thought, and with the advice of family and friends.

The Randomised Controlled Trial (RCT) is considered the benchmark for scientific rigor in proving whether or not a new treatment works. Its goal is to minimise bias and to allow for a clear comparison and definitive results. But, if you’ve been in the clinical trial world very long, you know what makes many patients hesitate to enrol in these trials—the possibility of receiving a placebo (an inactive substitute) instead of the experimental therapy.

And this brings us to the prevailing conundrum in the industry today: While RCTs are “good science,” are they always “good ethics” from the perspective of a patient desperate for effective treatment?

Understanding the “Why”: The Scientific Case for Placebo in Trials

Comparing a new drug to nothing (or a placebo that looks like the drug) is often considered the clearest way to prove that the drug itself is causing the observed effects, beyond any psychological (the placebo effect) or natural disease changes. Randomisation and blinding, where patients and often even the doctors administering the drug don’t know who gets what, prevent conscious or unconscious biases and preconceived ideas from influencing results.

On top of all this, trial coordinators feel pressure to use the RCT design because regulatory bodies like the MHRA, FDA, and EMA often specifically require placebo-controlled data for drug approval. I understand that this is not an excuse or justification, nor is it intended as such. I am merely explaining the scientific rationale behind the methodology of the RCT design.

The Patient’s Perspective: When Time and Hope are Critical

For you, as a patient, the stakes are high. The time of any patient is valuable, but particularly if you are experiencing a life-limiting illness such as advanced cancer or progressive neurological conditions, this specific trial may represent one of few remaining options.

The emotional weight of a possible placebo, a treatment that will not work is now added to the burden of the illness that you already bear. You feel that you’re losing valuable time, wasting your time, gambling on the chance that you might receive an actual treatment. You begin to feel that you are an experiment rather than a patient being cared for, and become discouraged before you even know the results of the trial.

Some patients feel that the whole process is unfair. They ask, “Why should my chance depend on a coin toss? Am I not suffering enough already? Why do they get the actual treatment, but I don’t?”

And then even beyond the physical aspect, you have the psychological strain of not knowing. You may have received the actual treatment, but you question every benefit you experience because you always have that doubt that it might be a placebo.

The Ethical Tightrope: Balancing Progress and Individual Need

“Clinical equipoise” is a term that the clinical trial world has come up with as a sort of standard for RCT ethics. It is the idea that RCTs are only ethical when there’s genuine uncertainty among experts about which arm (treatment or control) is better. But does this theoretical balance translate into practical application? What is the patient’s perspective?

Herein lies the conflict: The need for robust data for future patients versus the immediate needs and hopes of one current trial participant. Is it ethically sound to ask an individual to potentially sacrifice their chance for benefit now for the collective good in the future?

RCT designs have tried to use informed consent as a solution. Patients sign the forms, but do they—can they—fully grasp the emotional and practical implications of the placebo in trials arm amidst the hope for a cure and the stress of illness? Is consent truly free under such duress? Newer designs are introducing self-service pre-screening options for prospective participants. These advancements can help to identify your level of understanding and comfort and help you decide what is best for you.

Echoes from the Community

This isn’t a theoretical exercise. The emotional toll is real, as highlighted in recent discussions within patient communities on platforms like LinkedIn’ and a recent patient summit I was honoured to be part of where all stakeholders grappled with the ‘gamble’ of placebo in trials arms in critical situations. Voices in these communities often express frustration or heartbreak regarding the placebo dilemma, sharing personal stories or concerns online. The above introduction is from a LinkedIn’ post after I attended this patient summit, and is just a small sample of the support systems that are available for you. This is one of the responses to a question I posed in a thread in another LinkedIn’ discussion: I know MHRA are open to novel trial designs so that may be one option to overcome the issue you are facing. And I would always recommend talking to a regulatory agency if there are challenges in a programme.

What this tells us is the regulators or at least of them are willing to listen. Sponsors should ask WHY and do so early on to avoid the concern over delays. Asking WHY and doing so on a regular basis will make people think and may lead to a mindset shift.

Are There Other Paths? Considering Alternatives

I want to conclude with a bit of context. Placebo controls are not always used in all situations and are not always appropriate. When an effective standard treatment already exists, the new treatment should be compared against that – not the blank slate of a placebo.

There is an ongoing exploration of alternative trial designs that may mitigate the ethical burden in some cases. Some examples of these innovations are adaptive trials that can change based on evolving data, pragmatic trials that focus on real-world effectiveness, and trials that compare new treatments against standard of care.

Regardless of design, you will agree that clear, honest communication is needed in all clinical trials. Empathetic communication from trial coordinators about why the particular trial design was chosen and what it means for you will go a long way to alleviate some of the fears and uncertainty surrounding placebos in clinical trials.