Presented by: Adj Prof Skerritt and Robyn Langham Therapeutic Goods Administration
Presented at: Online
Presentation date: Wednesday, 1 March 2023
Presentation summary: This webinar will address the recent announcement by the Therapeutic Goods Administration (TGA) that medicines containing psilocybin and MDMA will be classified as Schedule 8 (controlled drug) in the Poisons Standard for specific conditions when prescribed by a psychiatrist under the Authorised Prescriber scheme.
JS - John Skerritt
RL - Robyn Langham
BE - Ben Noyen
I’m the head of regulatory engagement at the TGA, which is part of the Department of Health and Aged Care. I’d like to first acknowledge our traditional owners and custodians of the lands in which we’re all meeting today. Pay my respects to the elders past, present, and emerging. And I’d certainly like to acknowledge all First Nations people, wherever you are, those that joined us today in this meeting.
So I’d like to start by introducing our speakers. Our first speaker today is Adjunct Professor Robyn Langham. She’s a member of the Advisory Committee on Medicines. Professor Langham is now the chief medical advisor to the TGA. She’s a nephrologist and clinician researcher, who has spent much of her career in public hospital service as director of renal unit at St Vincent's in Melbourne, and subsequently is an academic and the head of School of Rural Health at Monash University.
We also have with us today Adjunct Professor John Skerritt, who heads the TGA, but also is the deputy secretary of Health Products Regulation Group within the Department of Health and Aged Care.
The group that John heads works to safeguard and enhance the health of all Australian through effective, timely, and risk-proportionate regulation of therapeutic goods, the control drugs, drug import, export, and production. Just to note, before I hand over to Robyn, there is… You may not have all your questions answered today or get all the information you’re trying to receive. There are options for you to contact the TGA for further advice through our contact centre.
Of course you can always have a look online as well. There are frequently asked questions, and there’s a guidance document as well on access to MDMA and psilocybin, and some guidance also on the Authorised Prescriber Scheme. So please do have a look at that if need be. So without further ado, I will now hand over to Robyn for your presentation. Thank you, Robyn.
Thanks very much, Ben. And welcome everybody. I would like to start by acknowledging the traditional owners of the land I’m on at the moment, to the Ngunnawal, people of the Ngunnawal nation, and also pay my respects to any members of the Aboriginal and Torres Strait Islander community who are with us today.
So my job is really to talk to you about the medicine, if you like, behind the two agents that are subject to a change in regulation that we’re talking about today, and that is MDMA and psilocybin. I’d like to start with the summary slide so that everyone knows what I’m about to talk about.
The important points here is that there are a growing number of randomised clinical trials that support the efficacy of MDMA in the treatment of PTSD or post-traumatic stress disorder, and also psilocybin in the treatment of resistant… In treatment-resistant depression. And there is potential benefit therefore for these two cohorts of people in our community for whom there are other treatments that are either not effective or are contraindicated, and that leaves them with few or no other treatment options.
So psychedelics themselves are a large group of natural, synthetic, and semi-synthetic compounds, with distinct pharmacological effects. They manifest their effects on conscious experience, and that may include an altered sense of time and space, or distorted perceptions of the environment.
There’s also a renewed sense of purpose and a loss of normal boundaries of the self that are often described as ego-dissolution, or some people talk to it about unravelling the mind, if you like, or opening up the mind, that are distinctive features of these compounds. To date, the biological mechanisms that underpin how they work on the brain are really poorly understood.
We do know the basic pharmacology. This is a little psilocybin molecule that’s sitting inside a notch of the serotonin receptor. And they’re predominantly to do with serotonin receptors or dopamine receptors and a few other receptors, and MDMA particularly with monoamine transporters.
Psychedelics and psychotherapy have been with us for a very long time. We know they’ve been used in religious or shamanic and spiritual ceremonies for millennia. But they were first studied in a number of clinical trials in the 1950s and 60s. LSD and psilocybin became more extensively used to facilitate progress in psychotherapy through self-reflection, ego-dissolution, and access to the unconscious material.
These compounds were eventually marketed under the brand names of Delysid for LSD and Indocybin for psilocybin by Santos during the 1950s and 60s for use in treatment of different psychiatric conditions in association with psychotherapy. But early studies really suggested there was safety in these compounds, even with very medically complex patients. However there was somewhat a lack of rigorous medical and rigorous scientific methodology. And with reports of adverse events, limited the reliability of these early findings.
And compounding this, there was widespread use of psychedelics for non-medical purposes, as particularly LSD was being used for illicit purposes, for non-medical indications, and with careless experimentation, they had a very negative outcome and stigma associated with the drugs.
They had a strong association with political activism in the counterculture of the 1960s, and eventually the US and other countries culminated in their criminalisation with acts, such as the Controlled Substance Act of 1970, under Nixon’s war on drugs.
So research went really quiet for a very long time, obviously, as people were not able to access the drugs, but there’s been quite a resurgence of research in the last decade.
And these organisations, among others, have been leaders in being able to not only fund research and clinical trial programmes, but also to be able to work more closely with regulators in order to construct clinical trial design, that was really to enable alignment with what regulation was required so that, eventually, they can be used for patients.
And this is the PubMed graph of the last few years of publications, even showing that it really peaked in 2022, with 2023’s numbers still rising, with increasing numbers of interest in the academic process.
I do want to talk a little bit, and a very little bit, about the critical role of psychotherapy and what it is we’re talking about today. This is not just the drugs themselves that are being useful, but the role of psychotherapy in being able to achieve the outcomes of changing the mental health status of a patient. I’m not the person to talk about it. I know that little is known of the science behind it.
But there is a little bit with the intrapsychic processes and the mechanisms by which psychedelic drugs are presumed to work in facilitating the psychotherapy or in general mental health.
And this little diagram at the bottom from the Monash University Neuromedicines Centre talks about the three phases of psychotherapy, which include preparing the patient for the process. The important process of supportive psychotherapy during the actual dosing, after a single dose. And then the subsequent supportive process of integration, where the patient and the therapist work together to process the psychedelic experience.
Before I go through some of the important clinical trials that have arisen recently, there are important challenges that we need to be mindful of in all psychedelic clinical research. And to date, there has been difficulty in ensuring adequate blinding. By that, I mean, how is it that we can use this drug so that nobody knows whether they’re on a real drug or not, to give a full formal scientific analysis of whether it works? It’s obviously really hard to deliver a placebo that gives you a psychedelic experience.
There’s also been overrepresentation in studies of patients who’ve previously used psychedelics, and some uncertainty in patient selection and insufficient follow-up. And there’s also a difficulty interpreting clinical trials as this is not just one drug that we’re talking about, not just one blood pressure medication, but it’s a combination of drug and psychotherapy.
And there’s also been a history of concerns over researchers and their own psychotherapy use, from concerns about bias and scientific integrity to this notion of excess enthusiasm for psychedelics, whilst it’s really important for a researcher to be really enthusiastic about their research, but also some commentary about whether or not even personal experience with psychedelics is actually necessary for those who provide the therapy.
And this publication I’ve listed down at the bottom doesn’t mention all of these as a means of picking the holes or debunking the research, but really is a way of trying to identify where the trip-ups might be, so that science and research and clinical research in this area can move forward to a good outcome.
So psilocybin itself, once you take it, it’s metabolised to a compound called psilocin, which acts, as I said, against the serotonin transporter inhibitor and a few others. And when it’s taken at high doses, it can cause a mild to profound change in your sensory perception with euphoria, and sensory illusions, and auditory and visual hallucinations. Those effects are really dose dependent. So the higher the drug you have, the more the effects. And also they last for about eight to ten hours.
There are also well described unpleasant effects, which can include feelings of seemingly unending experience, as well as some nausea, vomiting, and transient headaches.
The trials I’m going to talk about, these are used in association with assisted psychotherapy for a period of eight to ten hours. Sometimes two to three doses about a week apart. But all in controlled settings, in an inpatient setting, if you like, with trained therapists alongside.
So these are just a collection of some of the clinical trials that have been of note in the last few years. I’ve highlighted the bits that I think are important, so you don’t have to read them all. This top one here, which was 20 patients, everybody knew that they were going to have some psilocybin. Then they did a functional MRI that also showed as well as improving their depression scores, an effect that was really rapid, they also had some changes in an area of the brain called the amygdala, which was felt to be quite different to the activity of previous antidepressants.
This one here, which was treatment-resistant depression, published in The Lancet Psychiatry in 2016, one of the very first, again showed that depressive symptoms were markedly reduced even at one week.
And these other ones that have been randomised, double-blind, crossover studies in patients with depression and anxiety in terminal cancer, showed also that the effect was there, but that they were quite enduring. With that six-month follow-up, changes were sustained. And this study in six and a half months, 60% to 80% of participants continued with clinically significant reductions in depression or anxiety.
The concern, of course, was they were quite small numbers of patients, and these weren’t being compared to existing drugs that were on the market.
So this was the one that, I guess, the publication in the New England Journal of Medicine, quite a prestigious journal, of a couple of years ago, where psilocybin was actually directly compared to escitalopram, which is a common antidepressant that’s used in the community.
And it was a phase II study. So slightly larger numbers of patients at 59. And there was a group of patients that had two doses of psilocybin compared with a placebo, and another group of patients that had the daily dose of this antidepressant escitalopram and placebo, which was an inactive psilocybin drug. And psychotherapy, obviously, went along with this.
And even though you can see this graph here, where the blue is the escitalopram and the red is the psilocybin, it looks like there’s a difference. The statistics didn’t quite reach importance at the end of the seven week of trial in their primary outcome, but there were some other measures that indicated. But in a sense, this, while it was a promising study, didn’t necessarily show that the psilocybin was better than escitalopram.
A really recent paper just published in November last year, though, was this, again, a larger study of about 230 patients, all of them having had one dose of psilocybin, of a different dose. And you can see quite clearly here, at week 12, this is the blue line of patients that had 25 milligrams of psilocybin. One dose with psychotherapy having quite a sustained improvement.
So this was a really promising study that suggested in larger groups of people, that their depression scores dropped significantly on this dose compared to 1 milligram. Not so with 10 milligrams. But importantly, the higher dose they had down here on the adverse events, the more adverse events that they had in the sense of headaches, nausea, and dizziness.
So there are risks. People always talk about the risks of psychosis in the use of psilocybin. But in the trial setting, that’s not been the case that has been determined so far. And clearly, whilst you’re having psilocybin, someone who’s recently intoxicated with psilocybin does resemble a psychosis, it’s felt that hallucinogens such as psilocybin are not thought to actually cause this psychotic illness, but rather unmask a psychotic disorder in those who might be susceptible.
And it is the important part of a clinical trial that studies screen patients for a history of psychiatric problems, and they regulate the dose of the drug, and administer the drug in a controlled setting, with follow-up, and these safeguards really are intended to minimise the potential for adverse events.
That’s not necessarily the case in an uncontrolled community setting. There’s been this one study with an online survey of 2,000 people who answered yes to having had a bad trip after taking psilocybin mushrooms. And there’s anywhere up to 10% of these people said that their symptoms persisted for more than a year, and that 7.6% sought professional help for those symptoms. So again this is online survey. It’s not a really rigorous medical tool or scientific tool. But it is a guide for clinical practice, and it does point out potential concerns with the use of psychedelics at least in uncontrolled settings.
Let me switch now to MDMA. It’s a ring-substituted phenethylamine. I’ve practiced that one. Originally made by Merck and co in 1912 a haemostatic agent, but it was pretty useless as a haemostatic agent, stopping people from bleeding. And it sat on the shelves for over 65 years, until it was rebirthed and then recognised for its psychoactive activities. And this became a new class of agents called entactogens, affecting only partially, overlapping those of other psychostimulants and serotonergic hallucinogens.
In its early years, again, this was used by some psychotherapists to improve the outcome of psychotherapy sessions. It was associated with… It gave patients these feelings of incredible emotional wellbeing and was described by some people as a penicillin for the soul. But obviously these psychoactive problems led to use as a recreational drug. And in the mid-1980s, it was commonly accessed and distributed under the street name of ecstasy, and particularly popular for facilitating an altered emotional state at raves.
But because of concerns about this abuse liability and also some early reports of neurotoxicity in animal models, again the MDMA was emergently classified in the US as a temporary Schedule 1 substance, which is substances that are not to be accessed or used by patients for any medical indication, and that was permanently so in 1988.
So again, over the last ten years, this has been increased in its approach. We know more about the effects of MDMA and the receptors that it works through. And studies with healthy volunteers, it’s shown that it does give an easily controllable and reversible state of altered consciousness, characterised by euphoria, and empathy, and wellbeing, extroversion, positive mood, feelings of authenticity, interpersonal trust, compassion for oneself and for others.
But in the clinical population, it has been known to be associated with increased anxiety. And also in patients with post-traumatic stress disorder, the particular cohort of patients that this is important in treating, some painful emotions, such as grief and fear and rage, which again identifies the important role of psychotherapy with use.
Again, a handful of the most important clinical trials over the last few years. The first, I guess, important recognition was this one in 2011, which gave a significant reduction in PTSD severity disorder in a placebo-controlled study of patients, of small numbers of patients. This one importantly did a long-term follow-up at 12 months and recognised that in these 28 patients, 25 of them did not even meet this PTSD criteria once they’d followed up.
So this is a collection of smaller studies so larger number of patients. So not necessarily all the same approach. But again showed the number of participants who no longer met the PTSD criteria increased even from treatment exit, which was half or 56%, to the long-term follow-up, which was between 70 and 74 months, to 67%.
This publication, again, at the height of COVID, in December… Sorry, in June 2021, was really notable because this was the first phase III study. Larger numbers of patients. And the primary outcome was what’s called the CAPS-5, which was the Clinician-Administered PTSD Score.
And you can see here in the graph, the blue line is those that were treated with placebo, and the red line was those that were treated with MDMA-assisted therapy, and those scores were much lower after session three, session four, which was at, I think, six or seven weeks’ duration. And these were three preparatory psychotherapy sessions. The three doses of MDMA, about a week apart each, with a session, and then the nine integrative sessions.
Clearly the authors are being very excited about these findings. And this finding here replicated in other scales, called the Sheehan Disability Scale and the Beck Depression Inventory scale, very excited. Still noted that we need long-term follow-up.
So what’s happened? These two trials, I mentioned the one that was published with escitalopram and that particular one with MDMA, showed even at the height of COVID, Nature Medicine listed it as one of their notable advances of 2021, calling it psychiatry goes psychedelic. And the New York Times as well did a big article on this, about how a psychedelic drug passes a big test for PTSD treatment. There are still other studies underway, larger phase III studies, that we’re waiting for more information on, clearly.
I want to just finish by talking about the abuse potential of MDMA. There is some research evidence from animals that the level of abuse or addiction is there with MDMA, but roughly to, about that of cocaine. Having said that, there’s been a number of prospective long-term, what’s called, naturalistic studies of patients that show no evidence that those that have been treated with MDMA, will seek out and self-administer street ecstasy or other drugs indeed. But again, further evaluation on long-term risk is needed in order to be able to understand.
So let me finish, again, with my summarisation, which is that there is a growing number of randomised controlled trials supporting the efficacy of MDMA in the treatment of PTSD, and psilocybin in treatment-resistant depression. There is potential benefit for these two cohorts of patients, those with PTSD and treatment-resistant depression. They have no other treatments that are effective or for which they can still have them, leaving them with few or no treatment options.
I’m going to finish there and hand over to Professor Skerritt to talk to you about the regulatory side of things. Thanks, John.
Good afternoon, everyone. Thanks for your participation in this. Now these slides will be available to all the registrants and, indeed, more broadly on our website. So I won’t be going through a lot of the detail because I’ll be talking about regulatory issues. But I’ll just highlight, really, what does this scheduling decision mean? Because there’s been a fair bit of accurate information in the media, but there’s also been a fair bit of inaccurate information. So it’s worth clearing the air.
So I’ll talk about the decision process and what it means. What it means for potential prescribers, and also to remind people of the importance of clinical trials as well.
So our role at TGA is to provide a national system to manage quality, safety, and efficacy of medicines and other therapeutic goods. Now most medicines that are available to the public have been through an evaluation, a detailed, very detailed evaluation, for efficacy, safety, and quality. But there are pathways for certain so-called unapproved products. And the two substances we’re talking about today are not TGA approved.
Again, that’s been a bit of a confusion in the media. We don’t have a standard medicine that you buy in standard packaging and get dispensed from your local pharmacy, for example. Instead they’re available through special access pathways. In the case of MDMA and psilocybin, for particular uses, they’re available through the authorised prescriber pathway and clinical trials. We haven’t assessed the individual products for safety, quality, and efficacy.
Now where we got to is a long and drawn-out process. It’s funny, again, some of the representations would say, this was a very hasty and surprising decision. But the original application and between the various submissions, we had over 13,000 initially, and 7,000 in a second cycle.
And so this all started back in early 2021, maybe in late 2020, and the final decision was only made less than a month ago. And we’ve also been asked, why did the final decision end up different to perhaps some of the interim decisions? And essentially twofold. Firstly, we were able to… And I’m not the decision maker. I should explain. The decision maker is a delegate of the secretary, a senior medical officer. We have a number of potential delegates. So it wasn’t me, but I understand all the background.
And so firstly, we were able to put additional controls over and above what was in the application, such as requiring authorised prescriber access, and we’ll explain what that means shortly. And it only became apparent towards the end of the whole process that we were able to require in law that additional set of controls.
Secondly, in the last few months, and Robyn showed a study from November 2022, further evidence developed. As you’ll see here, back in December 2021, we did commission and publish an independent expert panel report. But during 2022, further evidence developed about the potential of these products for major depression in the case of psilocybin, and MDMA for post-traumatic stress disorder. So they’re the things that changed, that led to the final decision.
Now medicine scheduling is simply a system that enables controls for different medicines. As you’re aware, there are certain medicines you can buy at a petrol station or at a supermarket. Others from the front of a pharmacy. Others from the back of a pharmacy. Some require a doctor’s prescription. Others are kept under lock and key.
And so those schedules all have numbers, and there’s a group of substances that are considered prohibited drugs. What we’ve done is moved, for those two particular uses, psilocybin and MDMA to the controlled drug status, Schedule 8.
Now there is also an interaction with state and territory drug laws, and we have been working closely ever since the decision with states and territories to confirm the changes required in the coming months to their state and territory drug laws, and that’s why there’s a lead period of time. We are still four months away from the ability to make an application to use these things.
And we expect the state and territory departments, who we’ve been meeting with in recent weeks, to clarify any local additional legal requirements. There may not be any if they make certain changes. But at the moment, they’re going through checking that there’s not any legal conflicts and so forth.
Now Schedule 9 is really what’s known as the, really, the prohibited, to use plain English, the prohibited drug schedule, where Schedule 8 is what’s really known as the controlled drug schedule. And the difference is… There’s a number of differences. But you’ll see the difference in green for Schedule 8 is that these substances have an established therapeutic value, but there are issues such as risk of misuse, abuse, or illicit use, and the risk of dependence.
Schedule 9, the statement says that there’s no currently established therapeutic value. And the issue for PTSD and for treatment-resistant depression was the emerging and increasing levels of evidence that there was potentially establish the therapeutic value in certain patients.
Now for other uses, and I’ll talk about this at the end of the talk, we are encouraging clinical trials. And so until now, everything has had to be under clinical trials because of state and territory regulation. Schedule 9 drugs or these particular substances when used for, say, something such as autism spectrum disorder or bipolar, are still under Schedule 9, and therefore under state and territory regulation, are required to go through clinical trials, rather than this pathway we’re talking about today.
So what actually does change in four months’ time? The rescheduling for these two particular conditions or indications, to use a medical term. And the requirement is that a psychiatrist is the only authorised prescriber, and they’ll have to apply to a human research ethics committee. These committees, there’s 200 of them in Australia. Most major hospitals, health departments, as well as some private organisations has them, and they look up the detailed protocol. And then a submission also has to come after that to TGA to be an authorised prescriber.
And other access schemes, such as the special access scheme that’s been used widely for medical cannabis, are not available. And if it’s a use in something such as I gave the example of autism spectrum disorder, it will still be clinical trials only. And we also don’t anticipate the TGA would approve protocols where the patients actually take the medicines home.
These will be used under close supervision as part of a broader protocol, which will be specified in the application to the human research ethics committee and also looked at by the TGA.
Are we the first country in the world? Again, there’s been a lot of hype in the media, and I guess the answer is yes and no. There are some other countries that have already provided psychedelic medicines in what they often call compassionate access schemes. Closely supervised along the lines of what we’re talking about. But Australia is potentially the first in the world from a drug scheduling point of view.
So in the US, for example, these substances are still sit up in their prohibited drugs of addiction schedule, which in their system is Schedule 1. So we’re the first to take it from a prohibited schedule to a controlled drug schedule and emphasising that there are therapeutic purposes. So in that way, Australia does lead the world.
So the authorised prescriber grants the medical practitioner for particular indications with a lot more information around its use to a group of patients in their immediate care. So that means that they don’t have to come back to us for every individual patient, but the patient has to be taking the same protocol, the same medicine, and the same dosage. Or if a range of dosages has been approved, within that range of dosages.
So they can’t suddenly say, look, now I’m going to try it on patients who may have obsessive compulsive disorder. You can’t just suddenly change your indication, for example. That would be illegal. It would have to be done under clinical trial. And they report the number of patients and so forth. It’s free. There’s no application fee. We will absorb the cost. I don’t know how I will absorb all the work.
And as I said, it’s a two-step process. You got to go to the human research ethics committee first. There’s a list of those available on our website and on the NHMRC, the National Health and Medical Research Council’s website.
The prescribers have to have a specialist registration in psychiatry and a fellowship with the College of Psychiatrists, and I’ve talked about the two steps they have to go through. Now it’s not just a case of as soon as they get this, they can give it to any patients. There are requirements, where they have to consider individual patient suitability, and they also have to have looked at other treatment options.
So generally, this will be for treatment-resistant depression that has proven resistant to, say, SSRIs, SNRIs, and maybe even off-label use of some antipsychotics.
So how do you become an authorised prescriber? Step one is you go to the human research ethics committee, and this is the sort of thing that the application will have to control. Now notice that apart from things like who you are and what the product is, notice that this is the part which will have the major scrutiny with clinical justification and clinical protocol for which it’s used.
TGA will be reviewing that as well, but we have… We are not controlling clinical practice, and we will not go out and say, you must have lighting at this level. You must have this number of people. You must have this. You must have that. We will review that, but we are not designing the clinical guidelines around that.
So there’s a number of treatment protocols out there, used in Australia and internationally, and it will be for the applicant, the applicant psychiatrist, to discuss that with the ethics and research committee when they put together their application.
And of course, there will be safeguards that they’ll have to describe so the treatment doesn’t cause harm. And we’ve heard about the risk of providing some of these patients who have an established diagnosis of psychosis. So it wouldn’t be normally used in patients who have a strong history of schizophrenia, for example.
Likely, the treatment protocols will be similar to those used internationally. Likely, the doses and formulations, we’ll use similar ones to those both in the meta-analysis that we did, but also in some of the more recent publications, and the research area is evolving every day. And each application will be looked at on a case-by-case basis by clinicians at the TGA, as well as clinicians and ethics and other experts in the HREC or the ethics committee, as they call it for short. Then your authorised prescriber application has to come into us.
Again, there’s some overlap between the two. We have a special focus on looking at the clinical justification and whether other treatments have been attempted and failed. The governance over it. Recording of consent. Whether, as I say, other clinically appropriate options have been trialled.
And I’ve got to remind you that it’s not a carte blanche. It is not a case of, well, one patient at a private hospital… Sorry, one psychiatrist, say, at Albert Road or The Melbourne Clinic in Victoria has an authorisation, therefore any of their psych colleagues can prescribe. The authorised prescriber is only allowed to supply the product to specified patients under their immediate care. We may apply specific conditions on a case-by-case basis, and the authorised prescribers also have to report adverse events.
Now how do you actually get it? Or where do you get it, as the advertisement said a few years ago. At this stage, we expect that almost all, if not all, will be imported, then they’ll be pharmaceutical grade. And an import permit is required through the Office of Drug Control. And again, links to how you do that are available from the TGA website.
And we do allow substances to be imported and held prior to supply to individual patients. So if an importer can produce a justification that it might be used for 50 or 100 patients, a batch… And this will reduce costs of the actual drug used in the treatment protocol. It can be imported and held securely with an import permit. And again, good news, we work for free again. Import permits are free. I just have trouble getting people doing them on the weekends for free.
And I should add, we’ve had a lot of questions about local Australian manufacture, particularly psilocybin from mushrooms, and there’s even been stock market activity and some of the publicly and privately listed companies have got very interested in these developments. We are considering arrangements that will be put in place. There are already, under state and territory laws, permits in place to cultivate psilocybin-producing mushrooms. We’ll provide some further regulatory guidance later.
But at the moment, we anticipate that these treatments will be done with pharmaceutical grade, purified pharmaceutical product. And here’s the business about domestic… I do not encourage you to read the beginner’s guide to growing mushrooms in your own backyard. We will provide further guidance later, and there are clinical trials underway. But we’d be most unlikely at this stage to provide an authorised prescriber approval for products other than pharma grade.
Now we’ve been asked about GMP manufacture. Strongly preferred but not legally black-and-white, absolutely required. If evidence of GMP systems being developed and other forms of QA and QC systems being put in place so the product is a pharmaceutical grade product, we will look at that. I’ve mentioned botanical crude products.
We also discourage the use of extemporaneous compounding. We do not believe it is necessary because there are a number of international commercial organisations that have these substances available for use. And indeed in the previous few years, the proceeding few years, we’ve already issued import permits to import those substances for clinical trials in Australia.
Advertising controls. Just to remind people that these are prescription medicines, and prescription medicines and unapproved therapeutic goods are prohibited by law from being advertised to the public. So do not promote yourself as an MDMA or psilocybin clinic because you’re naming a substance.
Now of course you can mention this directly to health professionals, providing that information and that communication cannot be accessed by the general public. And of course a discussion during a consultation. If you’re a referring GP or a psychiatrist, you can mention these substances in a consultation because that’s not subject to the advertising rules.
But we really want those involved, whether you’re a practitioner or whether you’re a company, to be well aware of the advertising controls, because guess what? We will be watching.
You also can present information about efficacy and trials and clinical experience in a scientific or medical conference. That’s unlikely to be advertising. But again, just be really careful about crossing a line. We’re happy to help advise, as we have for medicinal cannabis, about what might and may not be appropriate from an advertising sense. And just to finish. We do want clinical trials to continue. Very important for Australia.
And of course, the other indications, whether it’s bipolar or whatever, are outside the current approval. So this is still the clinical trial pathway. And I’ve just listed some trials underway in Australia and internationally, and there’s a really exciting set of indications for which there are clinical trials. So it’s now time to turn over to question and answers, and I’ll go back to the hosts.
Thank you, John, Thank you, Robyn. So, John and Robyn, I’ll go over the first question. Will the TGA mandate specific qualifications for the professionals who are involved in this treatment, or will this remain a recommendation?
So the only mandatory qualification is, of course, the qualification of the prescribing psychiatrist. Now clearly the application to the HREC, to the ethics committee, and which we will also review as part of the authorised prescriber team… Authorised prescriber approval will talk about the team involved in providing the therapy.
The only mandatory requirement is… And clearly, that team has to be adequately qualified and appropriate. But we’re not going to write down detailed clinical guidance from a TGA perspective on the other members of the team, other than the prescribing psychiatrist.
Thank you, John. Will the TGA consider updating their guidance to include mental healthcare workers beyond psychiatrists and clinical psychologists, particularly given precedent within trials and relevant competencies?
Again, I think I’m just repeating my previous answer, but the absolute requirement, unless there’s another rescheduling application and it goes through the whole process, is for the prescriber to be a psychiatrist with a direct clinical relationship with the individual. Other issues about membership and qualifications of a team will be considered on a case-by-case basis, but we do expect that there needs to be significant professional skill among that team. I don’t know if Robyn has got anything to add, but I’m essentially repeating what I said in my previous response.
No, John, I think you’ve got it covered there. Our role here is to regulate the access to the medication, and the decision has been that this is the purvey of psychiatrists, registered psychiatrists in Australia.
Would you like to make any further comment on this next question? It’s just in relation to the training. Who would be regulating the training background of any non-psychiatrist importing psychedelic-assisted therapies?
The composition of the team, as I said before, Ben, would be going… Would be what would be put up when they look at the clinical therapeutic protocol that goes before the ethics committee, and also we would review. But we wouldn’t say, gee, you have to have a master’s degree and X years and all that. It will be reviewed, but we’re not going to be writing a list of different staff with different qualifications.
Perhaps I can add a little bit more on the process of the ethics committee, and I speak as a chair of a large ethics committee in a major hospital in Melbourne. There’s a number of these processes that the hospitals’ clinical ethics oversight committees have responsibility for.
And this is not a brand-new phenomenon that these processes will be getting used to or trying to oversee. Often, in larger hospitals, there’s a separate clinical ethics committee that will look at and assess and adjudicate risk and appetite for within the hospital. This is a risk clearly that would be borne by the institution that’s housing the procedure. So this is a pretty well-worn path, and ethics committees themselves are fairly used to being able to sign off and support processes where they are fair and reasonable and aligned with current clinical research activity.
Thanks, Robyn. The next question relates to the guidance document. Will it be permissible for the authorised prescriber to be involved in patient screening and treatment management but not in any treatment sessions themselves around psychotherapy or dosing?
I don’t think that that would meet the legal requirement for… I’ll go back to the wording that describes the role of an authorised prescriber, where it’s patients under their direct care. So I gave the example of a psychiatrist, one of many, at the Melbourne Clinic or at Albert Road, for example, in Melbourne, and we are actually talking about the psychiatrist who has that patient… The medicine also has to be held under the direct control of the person and so forth.
So, no, I think it is a direct prescriber-patient relationship, and the psychiatrist will be there at the initiation of the therapy session. And I think these things will be looked at quite carefully. It’s not a case of one psychiatrist in a whole private mental health facility or public mental health facility get an authorisation and the whole facility uses them.
So the next question is around… Is related to HRECs. So how will HREC decisions be harmonised? Will they be given any guidance from the TGA?
Robyn, do you…
Again, I guess I alluded to this one already. The processes by which new access, authorised prescriber procedures are assessed and reviewed are pretty well established. And the ethics committee of the respective organisation at which the procedure is going to take place will assess on their own basis in terms of the protocol that’s being proposed, being aligned with the current clinical protocols that are being used in clinical research in terms of the expertise and the experience of the authorised prescriber and the team that’s involved.
So it really is up to the individual ethics committees to be able to determine for themselves what the proposed protocols’ and the proposed practitioners’ capability is.
Just further question here on guidance. Will the TGA be issuing further guidance documentation prior to July 1? And if so, if we could please describe what these planned documents may be, how extensive they will be.
The only guidance that we have committed to release is about domestically manufactured product.
It is quite likely that other groups, whether they be clinical professional groups or others, will release guidance around it. We were quite deliberate in not saying, and here’s the clinical protocol. We’re not the regulators of clinical practice. And really, it’s more of a role of the clinical professional organisations to do that. So the only further guidance that we’ve foreshadowed relates to botanical product, especially for psilocybin.
Thank you. Will the TGA mandate the use of independently designed and monitored patient registries? If not, why not?
We have no legal ability to mandate registries. We think that if there is a move from a voluntary sense or some particular providers of a product… I know that some companies see this as an excellent opportunity to get real-world evidence on efficacy or otherwise of these products, additional to the clinical trial evidence, and that could support drug regulatory approval. They may establish systems whereby they record clinical outcomes for registries.
But TGA has no power to mandate registries. But we would really think that for the progress of this area of medicine, it would be great if we could capture the clinical outcomes, successful and unsuccessful. This is not going to be a silver bullet. There will be many people with treatment-resistant depression who do not respond favourably to psilocybin, or to MDMA, actually, for PTSD. Some, we expect and hope will. But it’ll be really great if the outcomes could be documented. We just have no ability to mandate that.
I think you’ve explained this to some extent already, but maybe it’s worth just revisiting. Could you please explain TGA’s reasoning behind suggesting that clinical psychologists are best placed to facilitate psychedelic-assisted therapies?
We’ve set the psychiatrists as the prescribers, and we made a comment that clinical psychologists do have significant relevant experience as part of a team. And clinical psychology is a discipline which, increasingly these days, has a minimum of master’s level qualifications. And so these folks have five to six years’ experience, and they’re very valuable team members for any group of people who have mental illness. And I think if you look at most of their trials and international experience, they’ve been valued members of a team.
So there’s another question here that refers to the guidance document, particularly the statement, the Therapeutic Goods Regulations 1990 provide an exemption for therapeutic goods to be imported and held prior to supply under the AP Scheme. Does this mean that import of product is possible prior to 1 July or after 1 July, prior to achieving authorised prescriber status?
We’d have to look at that. Generally, the intent of that has been, say, someone is applying for authorised prescriber over a period of a year or six months. They might treat 40 or 50 patients. It’s economically punitive to import 40 or 50 little parcels of medicine.
It may be outside the intent of the regulations to do that even before there’s an application for authorised prescriber. It might be a little bridge too far. So the intent at least, if not the black letter law, is for someone with an authorised prescriber authorisation or in the system to be able to import enough product for multiple patients.
Now the other thing is that import licenses can be conditioned. And so you could conceive a system where you might have HREC approval, and an authorised prescriber application is before us. They might be able to start the process of an import permit application, and it could be conditioned such that the material would have to be destroyed if they were not successful in getting their authorised prescriber approval, in which case they’d be takin a significant commercial risk, but they may be prepared to take it.
Thanks, John. So for registered psychiatrists with AP approval for prescribing, are there JMOs required to be registered in order to prescribe, as long as they are supervised under the psychologist with that authorised prescriber supervision?
JMOs. Okay. I was thinking genetically modified people. Again, sorry if I’m sounding like I’m repeating myself because I am, we are not sitting there saying, the team has to have one full forward, one half back, and what colours they’ve got to play in.
That is really what’s put forward in the package to the HREC. All we are saying, that in law, it has to be under the direct supervision and involvement of a psychiatrist. The rest of the team will be looked at by the HREC. We will also review it. So we’re not necessarily saying there has to be one junior medical officer or this many clinical psychologists and someone to clean up afterwards. That is for the applicant to put before the HREC.
So I have a compliance question here. So what compliance activities does the TGA plan to ensure that APs comply with the strict conditions applied to access to these substances?
Because of the nature of this, we do have a compliance branch with experienced compliance officers, and we will be following up on individual authorised prescriber applications. We do have powers in law if an authorised prescriber goes outside their approval, and we can therefore take compliance action against the individual. And we obviously still have an interest in monitoring that authorised prescribers are behaving appropriately and that there isn’t any crossover into other indications, for example.
Where are psychiatrists meant to get accredited training in PAT?
My understanding is that the College of Psychiatrists have part of their fellowship training programme in psychotherapy programmes, and there is also some other organisations that provide it.
Okay. The question here [overtalking].
Again, this is not something that we are necessarily regulating.
So can the advertising mention psychedelic? If it’s been down scheduled to Schedule 8, which is now controlled, does it need to be kept under wraps?
We’re not the United States. And in Australia, the advertising of prescription medicines is not, directly to the public, is not legal. So the same way another Schedule 8 drug is or group of drugs are opioids. So the same way it would be looked down upon by both us and potentially across the line, by both us and also the Medical Board of Australia… You can imagine a medical clinic saying, we prescribe opioids to patients.
Promoting the prescribing of a Schedule 8 drug would cross both the requirements under AHPRA and the medical board, but also the requirements under the TGA advertising code, where advertising of specific families or of individual prescription medicines directly to the general public is not legal.
Because again, from a good clinical practice point of view, and I realise I’m probably lecturing clinicians here, but that’s okay, it generally is not considered good clinical practice to go straight to the treatment as a whole rather than looking at the individual patient need.
There will be patients who are totally inappropriate for MDMA and psilocybin. There will be patients who tried other things and perhaps they’re a good fit to involving in MDMA or psilocybin-assisted therapy.
But I think it would be a big step backwards if these treatments were seen as either a panacea or a blanket therapy for everyone who has treatment-resistant depression and/or people who have PTSD. That’s not what the clinical evidence shows, and there’s not the trial evidence that taking a pill of one of these things will fix everyone with treatment-resistant depression. And so as a result, we don’t really want to see psychedelic clinics sprouting up.
Thank you. This might be the last question. We’ve run out of time. Could you provide some insight into what TGA guidelines people should be reviewing when considering domestic manufacture of these medicines?
For manufacture, we have GMP guidelines already. Quite detailed stuff. If you go to tga.gov.au, and you look under either GMP, good manufacturing practice, or just manufacturing, you’ll see a wealth of information on manufacturing. And indeed, later this month, we’re holding a large face-to-face education training information function in Sydney. It’s already got over 500 people coming to it, and there may be space for more. So you can certainly learn more about manufacture.
I did foreshadow that in the coming months, we’ll be putting out more specific information on locally manufactured product because there are some companies making product for use in clinical trials, potentially with state approvals, but the current scheduling is for the pure substances.
Thanks, John. And I might just take the liberty for one more question, actually. I’ve just noticed. The TGA guidelines refer to a single dose for the Authorised Prescriber Scheme. Several research protocols use multiple doses. Does the TGA guidance mean only one dose can be given?
No. Again, it will depend on the protocol. If it’s misleading, please call that out where it misleads into that view. I realise there are some protocols… And in fact, I think Robyn showed the results of a three-day trial. And so what it isn’t is a take-home trial, and again each dose has to be explained in the application to the HREC and in the application to TGA. But it’s certainly not a protocol where we expect people will be taking this medicine weekly for six months or 12 months, but we realise some successful protocols have two or three doses.
Thank you. Professor Skerritt, Professor Langham, I think we’ll just end it there. So thanks for your time and for sharing your knowledge. For those that have asked questions and they’re unanswered, and there’s a few questions still there, we will go through those. We will look at updating our frequently asked questions and possibly our guidance material as well to try to answer some of those inquiries that you’re making.
Otherwise I did mention some of the ways that you can find more information about this on the website, or contact us on our 1800 number, and we can either provide advice or get you through to some of the experts that can provide advice as well. So thank you very much for your time. Have good evening.
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