The Middle Way: Tech-Enabled Psychedelic Pragmatic Clinical Trials

A review of "Can pragmatic trials help safeguard the development of psychedelic medicine?"

👋 Hi, I’m Zach Haigney. I write The Trip Report to help us understand what the future of psychedelic science, medicine, and spirituality might look like under the force of rapidly accelerating digital health technologies.

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Today, I want to bring attention to a framework for psychedelic Pragmatic Clinical Trials recently put forward by Robin Carhart-Harris, Adam Gazzaley, Anne Wagner, Manish Agrawal, Jerold Rosenbaum, and David Erritzoe.

I think it’s a pretty significant idea that could affect nearly all stakeholders in the psychedelic movement.

We first touched on this idea in June of last year in Crazy Idea: Pre-Approval Pragmatic Clinical Trials.

Quick Summary

  • A group of prominent psychedelic researchers recently published a paper about a research methodology called Pragmatic Clinical Trials (PCTs)

  • Usually, PCTs occur after a treatment has been approved by the FDA in clinical practice to understand risks and benefits in the real world.

  • The authors present a framework for pre-approval PCTs of psychedelics in legal jurisdictions that leans heavily on digital health technology to learn more about real-world best practices.

  • The ideas in this paper point to potential near-term opportunities and challenges for researchers, clinicians, operators, investors, and philanthropists

  • Changing laws around access to psychedelics, the maturation of digital health technology, and changes in the measurement and treatment of mental health conditions make PCTs a logical Middle Way that creates access and generates actionable research.

An idea that I have been excited by since I first encountered it is that of pragmatic clinical trials (PCTs) of psychedelics.

Recently, a group of notable psychedelic researchers argued for this idea and laid out a framework for PCTs in Can pragmatic research, real-world data and digital technologies aid the development of psychedelic medicine?

The paper’s abstract (emphasis added):

“Favourable regulatory assessments, liberal policy changes, new research centres and substantial commercial investment signal that psychedelic therapy is making a major comeback. Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice. Here we suggest supplementing traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters. These recommendations are intended to help support the development of safe, effective and cost-efficient psychedelic therapy, which, given its history, is vulnerable to excesses of hype and regulation.”

Typically, PCTs fill knowledge gaps after a drug is approved and establish a treatment’s effectiveness. Confirmatory clinical trials are designed to evaluate the efficacy of a treatment to satisfy the FDA criteria1.

Confirmatory trials do not address significant knowledge gaps that, given the hype and expected demand for psychedelic medicine, should be addressed before FDA approval.

Pre-FDA Approval PCTs are a good idea because:

  • unlike most treatments under FDA evaluation,, psychedelics are already in wide use

  • psychedelics have a favorable safety/toxicity profile

  • they enjoy a broadening of legal jurisdictions and increased decriminalization momentum2

  • digital biomarkers and remote monitoring tools if used appropriately, can generate meaningful inferences

Confirmatory Clinical Trials

The type of study MAPS and other sponsors are running are designed to determine if psychedelic-assisted therapy is more effective than placebo-assisted therapy. This is the key question that the FDA will be evaluating to approve or deny MDMA-assisted psychotherapy for the treatment of PTSD. (The recently published findings of the MAPP 1 Phase III trial indicate things are on track.)

These studies compare two groups; one takes MDMA and undergoes therapy the other takes a placebo and undergoes therapy. Everything is the same except for the pill.

Neither participants nor study staff knows who gets the real thing and who doesn’t (in theory)— the well-documented issue of blinding is a significant challenge here and something that will increasingly face scrutiny of this kind.

Perhaps most importantly for this analysis is the participants must fit very narrow inclusion criteria that exclude most people that may ultimately undergo MDMA therapy after it is approved. This rigorous study design is known as a Double-blinded Randomized-Placebo Controlled Trial (DB-RCT) and is referred to as the gold standard of clinical research.

Such confirmatory trials are designed to test for efficacy (does it work?) under ideal circumstances (minimal variation in study participants). This is how we know if a new treatment is safe and that it works.

Basically, if MDMA is shown to be superior to placebo under these conditions, the FDA approves it,. Then doctors can prescribe it, insurers will cover it (in theory), and people with PTSD will have access.

However, confirmatory trials are very narrow in their focus. As the authors point out (emphasis added):

“Developers may be right to adhere to convention in delivering confirmatory trials, but, if resources and conditions allow, considerable benefits could be gained from more explorative study designs.

Such exploration may be best served by research that can address a greater range of questions of clinical and real-world relevance. Similarly, whereas confirmatory trials may choose to constrain eligibility and treatment criteria, pragmatic trials may benefit from broadening them, while maintaining a sensibly high-bar for (assumed) contraindication-related exclusion criteria.

In other words, confirmatory DB-RCTs are very narrow in focus, a narrow slice of the population compared to those who will ultimately receive the treatment in the real world and thus leave many questions unanswered.

In the context of a product that already enjoys substantial (and growing) use, there is an opportunity to employ a more suitable scientific methodology that can inform physicians, therapists, shamans, guides: (emphasis added)

“As has been the case with medical cannabis, treatment-seeking patients will look for guidance from clinicians who take theirs from scientific evidence. Liberal policy changes occurring prior to the conducting of sufficient research could create similar problems for clinicians as occurred with medical cannabis.

Such imperfect clinical scenarios could, however, also represent opportunities for innovative pragmatic and observational research. The creation of electronic data registries, e.g. for prescribers of psilocybin therapy in regions legally permitting (regulated) access (such as Oregon, USA), may be one appealing example, enabling the collection of valuable real-world data.”

Gold Standard Knowledge Gaps

Confirmatory DB-RCT’s establish the probabilistic efficacy of treatment —they do not tell us if the treatment will work (or harm) the next person who receives it.

Because of these design features, when a new drug enters the market, there are more questions than answers about how and in whom it works (or harms) in the real world.

Some questions include:

  • How does a new treatment compare to the current standard of care or other treatments?

  • How do people with multiple diagnoses respond to the treatment?

  • How do responses differ across age, sex, race, income levels?

  • What are the clinical outcomes of off-label use?

  • What therapeutic options do patients prefer when presented with an option?

  • What are the long-term issues related to the treatment?

  • How many people need to receive treatment for one to benefit, known as the Number Needed to Treat (NNT)?

  • How many need to receive treatment to harm one person, known as the Number Needed to Harm (NNH)?

Typically, such questions are answered in the real world after a drug has entered the market in Phase IV Pragmatic Clinical Trials.

This research phase is where practice guidelines are developed, and information that helps clinicians treat individuals is generated.

Pre-clinical Phase I Phase II & III Phase IV Pragmatic Trials

Source: Does it work for my patient? A pragmatic approach to building evidence on clinical effectiveness

For these reasons, the authors note:

Our view, however, is that data derived from pragmatic trials may be able to teach us more (than DB-RCTs) about how best to deliver the treatment and how it could impact on the lives of a broad cross-section of people. To be clear, the argument here is for the complementary value of pragmatic trials, not for their superiority over DB-RCTs. At the same time, however, we do challenge, as others have previously, the hierarchical preeminence of DB-RCT-derived evidence.”

The Curious Case of Psychedelics

Usually, when a pharmaceutical company brings a new drug through the FDA approval process, it is something new (not always), and only the people in the trial will have undergone treatment.

Such novel substances are usually discovered, developed, and owned by life sciences companies. The data generated by FDA sanctioned confirmatory clinical trials are the first indication to the medical community that this new drug is safe, effective, and might be useful.

Thus, confirmatory trials determine that a new treatment is safe and effective, and thus, the logical order is to conduct confirmatory trials before pragmatic trials.

Psychedelics present a situation in which it makes more sense to conduct both trial types, simultaneously given the unique features of psychedelic substances, their place in society, and what we already know about them.

Here is a non-exhaustive list of what makes psychedelics rather unique as objects of study and potential therapeutic tools:

  • Unlike most candidates going through FDA trials, psychedelics are widely used in society, and this use is increasing.

  • Psychedelics have a longstanding history that predates the notable counterculture period by thousands of years in almost every corner of the globe.

  • There is scientific literature from a short-lived period of clinical research in the 1950s and 60s that points to promising results.

  • These are not new molecules. The patent protection and thus investment framework is radically different.

  • Psychedelics, at least the first generation, will be delivered as adjunctive to psychotherapy and will require substantive infrastructure and trained therapists.

  • Regulation and policy changes are afoot, with decriminalization and licensed legalization frameworks already approved in several jurisdictions.

Clearly, psychedelics present a unique situation for regulators, clinicians, and individuals, and if we wait to fill in the knowledge gaps until after FDA approval, we are missing an opportunity. As the authors note:

“Exploration has special value early-on in a learning process; thus, it seems prudent in the context of psychedelic therapy that it be given consideration now, rather than further down the development path, when suboptimal parameters begin to undergo regulatory ‘lock-in’.”

Tech Enabled Pragmatic Clinical Trials

Here’s where things get interesting, in my opinion.

Two authors of the paper, Robin Carhart-Harris and Adam Gazzaley hail from UCSF’s translational neuroscience lab Neuroscape which has developed the most interesting and exciting digital health technology as far as I am concerned and thus come as authorities on matters of digital health. Fittingly, such a PCT framework would rely heavily on dgitial technology to aid in the data collection:

“Here we propose that pragmatic trials, data registries and electronic data capture will aid advances in psychedelic medicine by catalysing our understanding of best practice, which includes, but is not limited to, identifying and mitigating risks…

Easy to sample biometrics (e.g. via wearable devices or sensors and simple electroencephalography) and behavioural sampling (e.g. natural language and phone-use) could accrue large pools of objective data with potential predictive value.

If such studies and data registries are designed with careful consideration of data quality and fitness, pragmatic research could create significant value for various different stakeholders, e.g. scientists, clinicians, regulators, health care systems, payers and investors.”

We are in the early days of a digital revolution in healthcare. The tools available to patients, providers, scientists are increasingly applying evolutionary pressure to the institutions, incentives, and processes of care delivery and clinical research.

As it happens The National Academy of Sciences, Engineering, and Medicine is in the midst of hosting a four-part public series entitled Envisioning a Transformed Clinical Trials Enterprise for 2030 - A Workshop where stakeholders are gathering to mete out the key topics including:

  • Convergence of clinical research and clinical practice

  • Clinical trial data sharing

  • Incorporation of new modalities, such as digital health technologies, into drug research and development

In other words, this theme is not unique to psychedelic science and medicine. It just so happens that the psychedelic renaissance is coinciding with what seems to be a massive upheaval of the practice of science and medicine.

The recent advancements in digital biomarkers, biometrics, and tracking enabled by smartphone technology turn the process of data collection on its head from punctuated, before-vs-after, survey completion to the moment-to-moment passive collection of behavioral data.

What a time to be alive

With psychedelics, we have a situation in which the sanctioned path to access (FDA confirmatory trials) is limited in its ability to help us understand the real-world implications, while at the same time, there are growing numbers of people who are self-administering this treatment, in the real world.

Concurrently, the technology that enables wearables and biosensors that capture biometric data is coming of age.

Under this evolutionary pressure, the rationale for a framework of Pragmatic Clinical Trials for psychedelic therapy is very compelling because:

  • The demand exceeds the supply of opportunities to participate in sanctioned clinical trials.

  • There is a proliferation of legalization efforts that would enable pseudo-legal access.

  • The trials that are underway will generate data that is insufficient for clinical practice.

  • The tools that enable sophisticated data collection are in our pockets.

In closing, the authors note:

“Some might feel it premature to propose pragmatic trials for psychedelic therapy, as these are typically reserved for treatments that are already incorporated into clinical practice. However, we believe that it is right to begin such trials now, as policy changes are already afoot and could ‘get ahead of the data’, as occurred with cannabis, for example…

Rectifying this matter now may help mitigate risks associated with a too hasty scale-up of access. To achieve this, however, buy-in from multiple stake holders will be needed, including the public, policy makers and those in between, e.g. scientists, clinicians and investors. The motivation for doing so is to protect the sustainability of psychedelic medicine.”


“Efficacy can be defined as the performance of an intervention under ideal and controlled circumstances, whereas effectiveness refers to its performance under ‘real-world' conditions.” - A Primer on Effectiveness and Efficacy Trials