Crazy Idea: Pre-Approval Pragmatic Clinical Trials
***This post might be the most “Inside Baseball” that we’ve done to date but is a crucial area that everyone can contribute to and around which there may be early business/employment opportunities for clinics, therapists and clinicians.***
I was planning to write about the role of technology in psychedelic-assisted therapy and propose a weird idea but it turned into complete horse shit and speculation that needs a lot of work and wouldn’t help anyone.
I was afraid that I wouldn't have anything to go with today, then last night I listened to Robin Carhart-Harris (RCH) in his interview with Anne Phillipi at The New Health Club in which he proposed a concept that is new to me—Pragmatic Clinical Trials—to address two major pain points:
The extremely large, and growing, demand/interest for psychedelic-assisted therapy
The need for more extensive research on the broad categories of psychiatric conditions that many will be asking their doctors about, comorbidities, contraindications, etc.
This is a crazy relevant topic that has kinda slipped under the radar because so much focus of the access talk is about clinical research for FDA approval and Decriminalization efforts—but the idea of moving up pragmatic research is true outside the box thinking.
The pertinent portion of the conversation between Anne and RCH starts around 25:30.
Anne recounts how she gets multiple emails every day from people wondering about where, how, when they can get psychedelic therapy, or where they can participate in a study. They’ve tried everything, they read articles from Forbes, Vice, Fortune, etc. about how great psychedelics are for depression, etc., and many think they can just go to Imperial College and simply enroll in a study and it will be great.
But it’s not how it works and people are frustrated:
Anne: “How do you think this really big challenge can be handled? What is a good thing to suggest?
RCH: “The size of the demand to supply is ridiculous, people think “oh I can get this treatment by volunteering for a trial.” First of all, there's very restrictive criteria around certain trials… if you have depression you think you can get in but you can’t. So you have these very selective and constrained studies so that’s no solution to this issue…
One message is we’re just going to have to be patient and let the research happen…
One solution that I am suggesting at the moment is to… set up pragmatic trials which are different to the kind of trials that are being done to convince regulators like the FDA, EMA to license psilocybin therapy as a legal medical intervention for a particular disorder…
And so if you were to set up a pragmatic trial and you had resources to do it, which is of course a major determining factor, then you could potentially set up a trial with a broader inclusion criteria than a very constrained regulatory trial, and you could perhaps have broader criteria on the dosing protocol, meaning you could perhaps have more potential range of dosing sessions and you’re treating a trial like that more like a way to get a head start on understanding what this will look like when/if this does get licensed…
Pragmatic Clinical Trials
Pragmatic trials are typically performed after a drug is approved to provide data from real-world situations including comorbidities, interactions with concurrent medications, and effectiveness compared to other drugs and for other cases.
“there are “three key attributes of PCTs: (1) an intent to inform decision-makers (patients, clinicians, administrators, and policy-makers), as opposed to elucidating a biological or social mechanism; (2) an intent to enroll a population relevant to the decision in practice and representative of the patients or populations and clinical settings for whom the decision is relevant; and (3) either an intent to (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial or (b) measure a broad range of outcomes.”
The research going now by MAPS, COMPASS, and Usona are regulatory or explanatory trials. They are very restrictive and intended to provide a causative explanation for treatment outcomes for narrow diagnoses.
Explanatory research is not designed to offer insight to patients and physicians about the utility of this treatment in a broader category of conditions, or how certain subcategories of patients respond or establish more definite contraindications it is simply to prove causation and efficacy.
RCH points this out:
“you create this artificial condition to do the regulatory trials, the double-blind, randomized, controlled trials with very constrained parameters like one or two dosing sessions, fixed-dose, very selective population and then it gets through and all of a sudden clinicians and patients want it for this, that and a lot of different things and clinicians are thinking “should I give this off label?” And you are looking at a situation where there are a lot of unanswered questions…”
A similar, but slightly different differentiator would be “efficacy” vs “Effectiveness”. Explanatory/regulatory are efficacy trials (does it work?) while certain types of pragmatic trials would be considered effectiveness trials if they compared one treatment to another (rather than a placebo).
The pragmatic trials that RCH is suggesting would be broader than mere effectiveness trials and would include multiple variables to account for different dosages, conditions, comorbidities, etc.
The challenge is that pragmatic trials are typically done AFTER a drug is approved
However, at least one other person has thought about this challenge.
Jodi Segal is the co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins University (how about that) and author of The Prospect of Early Pharmaceutical Pragmatic Clinical Trials: A Background Paper which was written to address this very issue and advise on how to implement pre-approval pragmatic trials:
“Pharmaceutical and biotech companies have recognized that achieving optimal market access is not assured by focusing only on meeting regulatory requirements. It is increasingly necessary to design pre-market trials that provide the evidence desired by post-regulatory decision makers. While the demand for such evidence is recognized, there are few examples of pragmatic trials being done for drug licensing.
However, the primary focus of pre-approval clinical research is efficacy, (does it work?). Since the Kefauver-Harris Drug Amendments, or “Drug Efficacy Act” of 1962, this has been a primary requirement for drug approval.
It is only after approval that regulators seek safety data from a larger population in order to detect rare adverse events or long term use effects. These data often comes from safety surveillance systems or from data requested from the industry as part of risk management strategies.
Pre-Approval Pragmatic Trials
“One scenario is that the PCT is initiated early, at the traditional start time of phase III trials. FDA could make a decision to approve the drug based on results of, perhaps concurrent, conventional efficacy trials or could wait for the results of the PCT. If the FDA waits for PCT results, drug approval will be delayed, denying patients access to these medications during this time, and denying the manufacturer revenue from the drug”
(I am presuming based on the above that pragmatic trials are longer lasting.)
The problem, of course, is that drug trials are expensive and the burden of even more pre-revenue time and investment makes it even riskier for investors.
One idea that I have is so far out that it is probably impossible, but hear me out—because of the long history of human use, huge unmet need, and the dearth of treatment options there is the need for a new hybrid category of trial—something that combines Expanded Access, Compassionate Use and Pragmatic Trials earlier in the development phase—and here’s the kicker that will get me in trouble: patients can pay for out of pocket to participate.
Is that totally out of line? Are there ethical considerations?
What’s that you say?
This is batshit crazy?
Yeah, I know but I am trying to think about ways that we can leverage the known safety and large effect size of psychedelics with the dire mental health fucking crisis with some established loopholes/exceptions to kill two proverbial birds with one stone.
I’ll close with a final quote from RCH:
A similar thing happened with medicinal cannabis where it got through the system without sufficient research… to be able to address all of the questions patients would have when they come to their doctor and say “well, could cannabis help?” and the doctor is thinking “I don’t know because that question hasn’t really been addressed by the research.”
So what I am suggesting is not a perfect solution but is better than the present situation I think would be to set up some kind of multi-site pragmatic trial with broad inclusion criteria. Similar things have been done in other areas of medicine like in oncology where you have these master protocols that allow you to treat different cancers with the same treatment, and why not psychiatry? Why not psychiatry when there is so much overlap between psychiatric disorders anyway whether its OCD, eating disorders, depression, anxiety. And so logic and intuition suggest there may be some kind of nucleus here that’s common to these different expressions to psychological suffering… it seems to be this treatment is working for a lot of different things, it seems that way and therefore maybe that’s it’s future and if that’s its future can we set up some kind of research platform now that allows us to test that without it being this little bitty study over here and this one over here, why not try and have a bigger study?
Thanks for reading and have a great weekend,
Things may be different now, but worth noting that this approach was proposed for LSD research about 20 years ago and FDA was not supportive.
To me, this doesn't sound like a good use of money for a start up. But, with adjustments, it could be a good basic science project for an academic lab.
I think it would be much simpler in terms of ethics and regulatory red tape for a group not doing drug development (like the Hopkins or UChicago teams) to fundraise for study based on the RDoC framework. A study designed with this framework could look at general therapeutic effects that cut across diagnostic categories.
Having participants pay would be ethically perilous, but this should be relatively easy to raise money for. Arguably, the dubious work Fadiman and Stolaroff and crew were doing in the 60s can be read as an example of how having participants pay distorts incentives.
And using an investigator-initiated vs drug-company-initiated application emphasizes that this designed as basic research, which, given the statistics of heterogeneous samples, more likely to yield new hypothesises than conclusions.
Link to RDoC framework: https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/about-rdoc.shtml