Authors
Prof David J Nutt
Imperial College London; Drug Science
Tadeusz Hawrot
PAREA
Peter Hunt
Mind Medicine Australia
Dr Anne Katrin Schlag
Imperial College London; Drug Science
Published
August 6, 2024
MDMA [now called midomafetamine by the FDA] is a substituted amphetamine first synthesized in 1912 by Merck that has been developed over the past 30 years by the Multidisciplinary Association for Psychedelic Studies (MAPS) as a novel treatment for post-traumatic stress disorder (PTSD). It is administered in three doses at least a week apart, during a 14-week course of psychotherapy. Six phase 2 trials [Mithoefer et al 2019] as well as two large phase 3 trials [Mitchell et al 2021; 2023] have demonstrated clear clinical efficacy, even in patients who have not responded adequately to other treatments [Mitchell et al 2021]. These findings led the FDA to grant breakthrough therapy status for MDMA as a treatment for PTSD. Based on these positive findings the company Lykos was established to introduce MDMA into medical use. The first stage in this process is the submission of a clinical efficacy and safety dossier to the US FDA which will be adjudicated in August 2024.
As a prelude to this the FDA held a public advisory committee (AdCom) hearing in early June 2024. This committee almost unanimously rejected both the evidence of efficacy and the benefit-risk profile for MDMA-assisted therapy (MDMA-AT) submitted by Lykos. This decision surprised many in the field given that the clinical efficacy data had been available in peer-reviewed and often high impact journals [e.g. Mitchell et al 2021, Mitchell et al 2023] and appeared to meet the FDA requirements of two placebo-controlled randomised controlled trials (RCTs) for proof of efficacy. Moreover, there has been an urgent need for innovation in the treatment of PTSD for decades: it has been nearly 30 years since two SSRIs were licensed, and these rarely produce full remission.
An added clinical benefit of MDMA-assisted therapy is that the drug is administered just three times in total unlike other psychiatric medicines such as SSRIs, which are generally given chronically hence can carry an ongoing side-effect burden. This is often seen as a significant advancement in terms of massively reducing the total exposure of the person to the pharmacological ingredient. This lowers the risk of drug interactions, allergic effects, and tolerance development with the risk of withdrawal in addition to a reduced side-effect burden. Additionally, this limited dosing schedule could lead to significant long-term cost savings for healthcare systems by minimizing ongoing treatment expenses.
These data at face value fulfil the FDA rule that requires two placebo-controlled trials demonstrating efficacy and a positive benefit-risk ratio to permit marketing authorisation. The Lykos data showed this requirement was met with a between-subjects effect size of approximately 1 [a large effect size]. This is about 3 times greater than that of the only class of licensed medicine used for PTSD, the SSRIs (fluoxetine sertraline venlafaxine and paroxetine) [Hoskins et al 2018]. [Note the between subjects effect size subtracts the effect of the therapy from the effect of the therapy plus MDMA, leaving the effect only of the MDMA. A more clinically relevant effect size is the within-subjects effect size, 2.1 in MAPP1 and 1.95 in MAPP2]. The MDMA effect size is even more remarkable given that many of the patients in the MAPS trials were treatment-resistant i.e. had failed to adequately respond to both SSRIs and psychotherapy, a situation common for a substantial group of PTSD sufferers.
The high statistical significance of the clinical results indicates that some assessors voted against the therapy due to doubts about aspects other than the statistics. Perhaps it was the very uniqueness of this treatment that concerned the AdCom panel? The AdCom’s consumer representative Kim Witczak, said in an email "This is a new territory and it must be treaded carefully, the time to be cautious is now, not afterwards." Yet the flipside of being overly cautious means that suffering patients may be denied the opportunity of experiencing a medical therapy that could make a positive difference to their lives.
The Key FDA AdCom Concerns
We summarise 7 key concerns from the FDA AdCom hearing in Table 1 below. Each of these issues is addressable, as we outline in the following section. None alone should debar MDMA therapy, though an accumulation of doubts over each might explain the advisory panel votes. As Oreskes and Conway [2010] point out in their book “The Merchants of Doubt” the creation of doubt is a common way scientific facts become undermined in peoples’ minds, making policy decisions less straightforward.
Table 1 Key concerns from the FDA AdCom hearing
| How can a combination of medicine and psychotherapy be regulated when the FDA has no jurisdiction over psychotherapy? |
2. Blinding issues | Could the failure to blind patients to the active MDMA arm, combined with an expectancy of positive results in the MDMA treated group have biased the results? |
3. Potential for misuse | Given MDMA popularity as a recreational drug, could its misuse increase if it were approved as a medicine? A related concern appeared to be the fear that patients might seek out MDMA after enjoying its effects during therapy. |
4. Training and generalizability | It would be difficult to train enough psychiatrists and other therapists to ensure the generalizability of treatment efficacy outside of clinical trials. |
5. Risk of therapists' misconduct | Is there a risk of therapists breaking down personal boundaries, potentially encouraging sexual contact between patients and therapists. |
6. Long-term benefits | What are the long-term benefits of MDMA-assisted therapy, and how can they be assessed? |
7. Negative benefit-risk ratio | If MDMA treatment is ineffective the benefit-risk ratio will be negative. |
Solutions to the key concerns
1. How to regulate a treatment that comprises a combination of MDMA and psychotherapy.
The use of MDMA as a medicine in the MAPS trials was within a psychotherapy programme designed to help PTSD patients overcome re-emerging trauma emotions. This combination therapy is underpinned by neuro-imaging studies showing MDMA can limit overwhelming emotions when traumas are re-lived [Nutt and DeWit 2022]. Consequently, the pharmacological effects of MDMA enhance the effectiveness of the current gold-standard treatment which is extinction-based psychotherapy [Foa & McLean, 2016].
This approach of combining drug therapy with psychotherapy is not unique in psychiatry, rather it is the norm: psychiatrists often incorporate some level of psychotherapy with their patients as part of good clinical practice. There is a considerable research literature on augmenting medicine with psychotherapy showing significant benefits- for example, combining an antidepressant with psychotherapy in treating depression [Keller et al 2000]. In anxiety disorders where exposure psychotherapy is the established treatment approach, a range of different drugs have been shown to improve outcomes. For example, benzodiazepines were used to facilitate engagement in exposure therapy for panic/agoraphobia over 40 years ago and more recently d-cycloserine has been tested for similar reasons [Otto et al 2010].
In PTSD both paroxetine [Schneir et al 2012] and yohimbine have been found to significantly augment exposure therapy [Tuerk et al 2018] though no such combination therapies have yet been approved for PTSD. This is because, until the MAPS/Lykos initiative with MDMA, no attempts had been made to gain marketing authorisation for such treatments. However, combination therapies are approved in other psychiatric indications. For instance, in 2013 the European Medicines Agency [EMA] approved nalmefene combined with a psychological support package for binge drinking [EMA 2013]. More recently both the FDA, EMA and Therapeutic Goods Administration (TGA) have approved esketamine for treatment-resistant depression [FDA 2019], but explicitly without a psycho-therapeutic component.
Esketamine is an interesting comparison case for MDMA because both drugs, as well as the widely used parent compound racemic ketamine, have powerful subjective and objective features like those of serotoninergic psychedelics such as psilocybin. Indeed, the extent of altered consciousness produced by esketamine/ketamine is considerably greater than that produced by MDMA. This potentially powerful psychoactive effect was the reason the FDA mandated a Risk Evaluation and Mitigation Strategy (REMS) system for esketamine, requiring more extensive pre-dose preparation and patient advice along with constant patient monitoring throughout the altered state [usually a few hours] and a careful assessment of cognitive function before allowing the patient to return home.
Like MDMA, esketamine/ketamine are controlled drugs in common recreational use and in the case of ketamine showing significant tolerance and dependence potential. However, because ketamine is a vital licensed anaesthetic it is controlled at a lower level (schedule 3) than MDMA which is in schedule 1. Being an approved medicine for one indication allows ketamine to be used “off-license” also known as “off-label”, in other indications where there is a good rationale – e.g. in psychiatry for treatment-resistant depression and other disorders as well as in other branches of medicine e.g. pain control. In contrast because it is in schedule 1 MDMA cannot be used except, with special permission, in research which is why it was rescheduled for restricted clinical use in Australia.
The initial use of ketamine in psychiatry targeted addictions [Krupitsky 1997] and then treatment-resistant depression [Berman et al 2000], but it has now evolved into use in many other disorders such as OCD and anorexia. At first ketamine was given without any specific psychotherapy rather like ECT (indeed it was often colloquially called liquid ECT]. However, because of the successes of psychedelic-assisted psychotherapy with the serotonergic psychedelics especially psilocybin [Carhart-Harris et al 2016, 2021] the potential of gaining extra therapeutic benefits from adding psychotherapy to ketamine treatment has since been explored with significant success [e.g. Grabski et al 2022]. Now this combined approach is becoming more common because ketamine also induces a mental state conducive to psychotherapy. Similar to the serotonergic psychedelics ketamine also promotes neuroplasticity, which is believed to solidify therapeutic insights. Nevertheless, a large number of clinics provide esketamine and/or ketamine without accompanying therapy.
Despite the growing evidence-base of efficacy to date the ketamine/psychotherapy combination has not been submitted for marketing authorisation to any regulatory body, probably for commercial reasons such as the difficulty in patenting a treatment with such an established drug.
The Lykos submission is the first instance where a combination of drug plus psychotherapy has been submitted to the FDA for regulatory approval [nalmefene was only submitted for approval to the EMA]. This scenario creates uncertainty for regulators as they have no direct precedent and lack the authority to adjudicate on the psychotherapy component.
2. Blinding and expectation
During the hearing the issue of unblinding was introduced as a major concern. This was surprising as the MAPS design had previously been approved by the FDA as blinding is not typically a primary concern in trials of other medicines. A recent analysis of drug treatments for PTSD found that blinding was not assessed in the majority of these trials, yet some medicines were approved based on significant clinical effects [Hoskins et al 2015].
Ketamine and esketamine, which produce psychoactive effects that are noticeable to patients, faced similar challenges. Their trials were similarly unblinded, yet this did not prevent the licensing of esketamine [FDA 2019]. This raises the possibility of a bias in favour of esketamine or depression (or both) compared with MDMA and PTSD. Similar biases were initially observed in the preliminary expert reviews of MDMA (and psilocybin) in Australia but were later corrected in the TGA decision [Hunt 2023].
The issue of blinding and expectation with MDMA in part stems from the misconception that knowing you have received a potent stimulant like MDMA or a psychedelic like psilocybin could lead to improved outcomes even if the drug itself lacked therapeutic activity, essentially making MDMA a super placebo.
This explanation is unlikely for a number of reasons. Many of PTSD patients had not responded to prior “proven” psychological and medical treatments suggesting that their hope/expectation of MDMA’s impact must differ. Additionally, it is questionable that expectation effects occur with this group when similar effects are difficult to achieve with other hard to blind drugs (Szigeti et al 2024).
Rejecting the data might imply that the panel disbelieved the patients self-reported outcomes, suspecting that those who received MDMA exaggerated their responses. The alterative explanation, that the placebo group underreported their improvements, seems unlikely since their responses were consistent with placebo groups in similar trials. [NB: the placebo responders in the Lykos Phase 3 studies received substantial therapy with an inactive placebo and their outcomes were better than those in other studies since PE and CPT has roughly 50% dropout rates with very low dropout rates in the Lykos Phase 3 studies].
Perhaps the advisors thought patients exaggerated their response to treatment to make MDMA appear more effective than it actually was? This possibility may have stemmed from reports by some patients that they were “encouraged” to be positive about the treatment effects, though it is not clear if these were all in the MDMA group or whether that influenced their decisions. Considering this as an insult to the patients who attended the hearing and reported major benefits it is unlikely that so many would have independently engaged in systematic fraud to skew the published data.
Moreover, the panel might have been unclear as to what other mechanism might explain why the MDMA group did so much better: was it the MDMA, the psychotherapy or their combination? Since the psychotherapy was consistent across both groups we can eliminate it as the sole factor. Was the psychotherapy needed or could MDMA alone have sufficed? Perhaps, but it would likely be unethical to administer MDMA without psychotherapy to patients dealing with severe trauma as this could destabilise them if proper psychological support was not present. Moreover, there is no scientific basis to suggest that just 3 doses of MDMA given without psychotherapy would be effective. We know from testimonies at the hearing how highly patients valued the psychotherapy they received. An example from another branch of medicine would be knee replacement surgery. This could be done without the use of analgesia or anaesthesia but patients would almost certainly have better outcomes if given those. Conducting a comparison trial without psychotherapy would be unethical and likely impossible as patients would refuse to be randomised to the medicine-free group.
3. Misuse risks of MDMA
Another issue raised by the panel was the fear of abuse and dependence on MDMA, which is summarised below (please see below and Table 2).
MDMA and abuse risk
The DHHS has an eight factor check-list for determining abuse risk:
The drug’s actual or relative potential for abuse.
Scientific evidence of its pharmacological effect, if known.
The status of current scientific knowledge regarding the drug or other substance.
Its history and current pattern of abuse.
The scope, duration, and significance of abuse
What, if any, risk there is to the public health.
Its psychic or physiological dependence liability.
Whether the substance is an immediate precursor of a substance already controlled.
Table 2. MDMA addiction risk from three positions:
Data from the recent MDMA trials | Data from recreational use of MDMA/ecstasy | The psychopharmacology of MDMA in comparison with other drugs of abuse |
In the last three decades, MDMA therapy has been studied extensively as a treatment for PTSD, which has now completed phase 3 development and is currently awaiting licensing decision from the FDA. Smaller pilot studies have also examined the potential role of MDMA therapy in treating addictions (specifically Alcohol Use Disorder (AUD)) and Social Anxiety Disorder in adults with autism. The phase 3 trial by Mitchell et al (Nicholas et al. (2022)) in patients with severe PTSD did not show an increased risk of substance use or dependence among participants, as assessed by the Drug Use Disorder Identification Test (DUDIT) and Alcohol Use Disorder Identification Test (AUDIT). Specifically, there was no increased MDMA use observed during and 2 months following the treatment. In all the MAPS pilot, phase 2 and phase 3 studies of MDMA-PTSD, there have been no cases of participants craving MDMA or exhibiting drug-seeking behaviours following participation in trials. Also, data from a study of MDMA- in patients with an addiction (AUD) demonstrated the same lack of evidence of MDMA addiction following treatment in the trial (Sessa et al 2021). | There is a high prevalence of use of ecstasy in UK – second only to cannabis, with an estimated 800,000 MDMA users every week in the UK. This high figure contrasts starkly with the very low reporting of MDMA as the primary drug of abuse in UK addiction treatment centres. Only 424 such cases were reported in community drug services, and zero cases of MDMA were cited as the primary drug of addiction in UK residential treatment centres. This compares favourably with other ‘new’ recreational drugs (cathinones, ketamine), which within 12-months of appearing on the recreational drug scene, saw multiple cases of addictions in community and residential rehab centres in the UK. The Global Drug Survey (GDS) estimates that around 2-3% of MDMA users use it on a continuous basis, similar to ketamine (GDS 2022). | MDMA primarily releases serotonin with minimal dopamine release compared to substances with higher addictive potential, suggesting it may not produce the same reinforcement mechanisms that contribute to addiction in drugs like cocaine, opioids, or nicotine. This is likely due to lower activation of the brain's dopamine system, which is associated with compulsive drug-seeking behaviour and addiction. Additionally, serotonergic psychedelics have low/no dependence propensity and indeed can be used to treat addiction. |
The concern centred on the experience of euphoria during therapy as if this would explain the therapeutic effect and also induce non-patients to seek out therapy. Both ideas are baseless. MDMA therapy in PTSD is hardly pleasant – as one MAPS participant remarked after a gruelling session “I don’t know why they call this ecstasy”. Further, the drug is only given three times which minimises the likelihood of dependence.
Decades of recreational use have shown that dependence risk is low and rarely leads to people seeking treatment. Even the National Institute on Drug Abuse (NIDA) refers to it as only “potentially “addictive [NIDA 2024] Moreover there is no evidence of increased use after MDMA therapy in recent trials [Nicholas 2022] (it even reduced other drug use). There is no signal of increased use even where it has been used to treat alcohol addiction [Sessa et al 2021].
The illegal status of MDMA may have distorted thinking about its harms due to the disapproval of its recreational use. For political/moral reasons MDMA has been vilified more than most recreational drugs even to the extent of publishing false data [Knight 2003].
Cutting edge analysis using multi-criteria decision analysis (MCDA) methodology by four independent international expert groups has all scored MDMA’s harms as lower than most other recreational drugs and well below those of alcohol and opioids [Nutt et al 2010, van Amsterdam et al 2015; Bonomo et al 2018, Crossin et al 2024].
Drug-induced liking and “highs” are more significant with opioid analgesics than with MDMA, yet many opioids have been licensed. This raises the possibility of a subconscious stigma - do regulatory committees perceive physical pain as more “real” and worthy of treatment than the psychological pain of PTSD with its high suicide rate? Even in the unlikely event that some medicinal MDMA leaks into the illegal market the risks would be minimal compared to those of opioids.
Similar choices have already been made in favour of other medications known for substantial recreational misuse. Marketing authorisation has been given for amphetamine stimulants in ADHD, dopamine agonists for Parkinson's disease and most recently ketamine (in the form of esketamine) for treatment-resistant depression. Additionally, NIDA is currently requesting studies with ketamine for addictions, raising questions about whether the AdCom’s decision will deter this research avenue.
Clearly the critical issue should focus on the benefit-risk assessment, not on the fear of some patients seeking either more therapy or illegal sources of MDMA. Perhaps AdCom thought that approving MDMA as a medicine would undermine current anti-recreational use prohibition rhetoric and policies.
In over 2000 therapeutic applications of MDMA in the last 30 years there have been no recorded cases of patients developing an addiction to MDMA. Moreover, despite the widespread recreational use of ecstasy/MDMA in the UK over nearly 40 years, relatively few people present themselves to UK drug services, and levels of use have remained similar [ONS, 2023].
The low risk of addiction is probably because MDMA differs in its psychopharmacological profile from other stimulant drugs of abuse being much more serotonergic.
4. Training of therapists
Although therapists’ training could be a limiting factor in rolling out the therapy, MAPS and various other groups e.g. Mind Medicine Australia, have ongoing programmes that have trained hundreds of psychiatrists and psychologists in this type of therapy.
Marketing authorisation for MDMA could be issued on the condition that only registered and trained therapists are allowed to prescribe and treat with MDMA, as is the situation in Australia [Nutt et al 2024].
5. Risk of therapists’ misconduct: boundary violations
MDMA therapy is complex and involves extensive patient-therapist interaction, with each medicine session lasting up to 8 hours in total. This not only presents a challenge to both parties but also heightens the risk of transference, which MDMA may further enhance through its effects on empathy and trust. Similar issues arise with other drug-therapy treatments especially those involving psychedelics like psilocybin.
The MAPS programme has faced criticism due to an incident of clinical malpractice involving a therapy team and one patient which resulted in a sexual relationship between the patient and one of the therapists. Although this was an isolated incident within the MAPS trials, it has been widely reported as evidence that MDMA therapy is untrustworthy.
However, such patient-therapist boundary violations should not undermine an entire novel class of therapy. They can be substantially reduced by recording (and fully reviewing) every session for quality control and for in depth review if complaints are made. MDMA therapy is not intrinsically more risky than other forms of psychotherapy. Unfortunately, there is a lack of transparency about the harms associated with psychotherapy in general [Nutt and Sharpe 2008] but the dual-therapist approach used by MAPS considerably mitigates this risk.
The safety of alternative psychotherapy treatments for PTSD should also be taken into account. Prolonged exposure therapy can be effective for those who can tolerate it, but many cannot, leading to drop out rates over 50% [Ford et al 2018]. In contrast, MDMA therapy may enable patients to remain in treatment and therefore experience better outcomes.
6. Uncertain long-term benefits
This question arises with all new medicines where funding limitations or need preclude very long-term studies. These are usually conducted as Phase 4 after marketing authorisation. MDMA therapy should not be treated differently especially as there is already 20 years of experience with its use in phase 2 equivalent clinical trials, showing evidence of enduring efficacy for several years [Jerome et al 2020, Mithoefer et al 2013].
7. Negative benefit-risk ratio
Having voted 9-2 that MDMA treatment was ineffective it was not surprising that the panel then voted 10-1 that the benefit-risk ratio was negative. But the risk assessment approach utilised is questionable. The AdCom was asked to make a binary yes-no vote on both the efficacy and benefit-risk of MDMA which is poor practice particularly with a complex and novel treatment. Rather, there should have been some estimates of confidence in each person’s decision. A better approach would have been to use one of several modern benefit-risk methodologies [Mt-Isa et al 2014] or a full MCDA could have been carried out as developed for the EMA [Phillips et al 2011].
Asking an ad-hoc committee to address the complex issues raised by a new-in-class drug with a novel treatment programme in a one-day hearing is rather simplistic, raising the question of the validity of subsequent decisions? Taken together, it appears the assessors’ votes were based on several factors. The first being a common fear for many new drugs [especially it seems for psychiatric ones] that it is better to err on the side of caution and find reasons to reject. These reasons were inculcated by the regulators, raising multiple different doubts, none of which alone would be enough to block a positive decision but together they created sufficient uncertainty to support a negative vote.
Other factors to be considered by the FDA
International developments
Notably, supportive data from other countries were not considered important because other national expert groups had previously come to the opposite conclusion, that MDMA is a viable medicine (for some patients). In Switzerland MDMA has been allowed on a compassionate-use basis for several decades, when used by registered psychiatrists for patients with treatment-resistant disorders [Donauer 2022].
In 2023 the Australian equivalent of the FDA [the TGA] rescheduled MDMA to allow its use for treatment-resistant PTSD by approved psychiatrists [Nutt et al 2024] on the grounds of positive benefit-risk analysis.
In June 2024, the same week of the FDA meeting, the Dutch Commission on MDMA, established by the government and comprised of experts from psychiatry, medicine, criminology, prevention and law, issued its recommendations, concluding that “with what is currently known, there appears to be sufficient scientific evidence for the effectiveness and safety of this form of therapy” and “the government must act expeditiously to enable the therapeutic use of MDMA”. It decided that until MDMA-assisted therapy is registered in the Netherlands, the best way to provide state-of-the-art treatment is through a large, systematic naturalistic study [van den Brink 2024].
It is unclear if the AdCom knew of these decisions and the full FDA hearing in August may well come to a different conclusion to that of the panel. The final positive Australian TGA decision was preceded by negative opinions on some of the same key issues, which were exposed as flawed by expert feedback [Hunt 2022].
Professional bodies’ opinions
Both the original Australian and the current FDA opinions were likely influenced by the less-than-positive comments from the national professional psychiatry bodies [the APA and RANZP respectively]. These opinions on MDMA contrasted with these bodies’ previously more positive support for the licensing of another psychedelic drug esketamine [APA 2019; RANZCP 2022]. MDMA was assessed as having a weaker clinical evidence base and being more prone to abuse than esketamine.
In the Australian case a detailed critique of the arguments made by national psychiatrists concluded that a degree of bias had been applied against MDMA when compared with esketamine and that the evidence base for MDMA safety and efficacy was the stronger of the two [Hunt 2022]. These corrective assessments likely contributed to the TGA revising its decision and approve MDMA.
In addition to the APA report the FDA hearing was preceded by a well-publicised negative report by the Institute for Clinical and Economic Review (ICER) [2024]. This raised many of the concerns listed above and concluded that MDMA therapy would not be cost-effective so it would likely not be reimbursed by health insurers. Lykos has not yet publicly rebutted these criticisms which may have led some on the AdCom panel to assume they were true.
The way forward?
It is now up to the FDA to pursue the final stage of the decision-making process. They are at liberty to disregard any or all of the panel’s recommendations and we hope that this analysis may help them in their deliberations. A decision by the FDA against the Lykos application, will cause further challenges.
The huge unmet need for new and better therapies in PTSD will remain, with many patients likely to either continue to suffer, potentially committing suicide, or seeking out less safe underground therapy.
We have previous experience with similar challenges with new medicines. The most famous is that of the first drugs for HIV, the access to which was too slow for patients who were dying, prompting the creation of the accelerated approvals process by lobbying the FDA for faster regulatory process and the NIH for more research [History 2022].
If MDMA does not get marketing authorisation, a model might be based on the August 2023 decision of the US Department of Health and Human Services (DHHS) to move cannabis down from Schedule I to Schedule III alongside ketamine and buprenorphine. The decision was based on an eight-factor analysis of abuse related harms [please see Table 2] and an overview of clinical use. This review was led by DHHS with input from various agencies including the FDA who agreed that cannabis met the criteria of commonly accepted medical use (CAMU) so was de-facto a medicine hence could not stay in Schedule I. Schedule III was seen as commensurate with its low abuse potential. Current research data for MDMA in PTSD are almost certainly stronger than any medical cannabis product so the same decision could be reached, as was done by the TGA in Australia.
Funding
Conflicts of interest
List of abbreviations
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