In September 2020 Australia’s independent medical product safety regulator, the Therapeutic Goods Administration (TGA), rejected an application by Janssen Cilag, the manufacturer of Spravato (a nasal spray containing ketamine), to approve its use for ‘treatment resistant depression’. Spravato is taken along with an oral antidepressant. It is supposed to be self-administered by patients under the supervision of a doctor.
The TGA decided that there were 'a number of irresolvable methodological issues' with the evidence Janssen Cilag submitted and concluded 'there was a lack of robust data' demonstrating efficacy. (Therapeutic Goods Administration pages 11+42)
In reaching this decision the TGA had sought input from the Advisory Committee on Medicines (ACM). The ACM advised that it was 'concerned about lack of robust evidence to support the efficacy of intranasal esketamine for the proposed indication' and concluded:
Spravato has an overall negative benefit-risk profile for the proposed indication, as the evidence submitted did not satisfactorily establish the efficacy of the product with certainty. There is also doubt about the practicality of the RMP [Risk Management Plan] to support the management of significant safety and toxicity concerns. (Therapeutic Goods Administration page 41)
After receiving the ACM advice the TGA 'encouraged' Janssen Cilag 'to submit any new data it might hold on a properly designed clinical trial'. However, 'rather than provide the required new data on properly designed clinical trial' Janssen Cilag provided data from an incomplete, unblinded drug trial and a re-analysis of existing data. The TGA remained unimpressed and rejected Jansenn Cilag’s application. (Therapeutic Goods Administration page 41)
However, for the purposes of section 60 of the Therapeutic Goods Act, corporations like Janssen Cilag are 'a person' and 'a person whose interests are affected by an initial decision made [by the TGA] under the Act may, by notice in writing given to the Minister, request the Minister to reconsider the initial decision'.
In January 2021 and despite both the ACM's and the TGA's negative assessments, the Morrison Government Health Minister Greg Hunt, via a delegate acting on his authority granted Janssen Cilag's request by overturning the TGA’s decision and approved Spravato. (Therapeutic Goods Administration Pages 12+42)
Between July 2016 and June 2020 Janssen Cilag donated at least $147,400 to the Liberal Party (Self-generated report from the Democracy for Sale Website). The total figure could be much higher but because of Australia’s incredibly lax political donation laws we will probably never know the full amount donated.
According to the Department of Health the Minister's overrule of the TGA decision was based on an alternate interpretation of the same trials that the TGA and ACM considered, and advice from unnamed expert/s chosen by Janssen Cilag that 'commencing esketamine [Spravato] simultaneously with a new oral antidepressant likely reflected optimal clinical practice'. Apparently Minister Hunt's delegate was persuaded 'it may be unethical for patients with treatment-resistant depression to be left without any antidepressant treatment'. (Therapeutic Goods Administration page 44)
In contrast, it was obviously considered ethical for a Government to overrule the independent regulator’s decision and intervene in favour of a drug company that is a political donor on the basis of advice of an expert chosen by the drug company.
Throughout the Covid19 pandemic both Prime Minister Morrison and Health Minister Hunt have repeatedly reassured Australians that they rely on the independence and expertise of the TGA. Yet in the case of Spravato the Morrison Government trusted their political donor Janssen Cilag, rather than the TGA.
Note: The full reasons given by the TGA for its' decision to reject Sparavoto's approval and the reasons cited for the Ministerial overrule of the TGA decision are detailed below in Appendix 1.
The ACM's and TGA's concerns about the lack of robust data demonstrating efficacy are not the only reason to be worried about Spravato. As demonstrated in the extract (below) from the Prescribing Information produced by the US FDA, Spravato carries the highest possible Black Box Warning for sedation, dissociation, abuse and misuse, and suicidal thoughts and behaviours.
Of particular concern is the evidence about Spravato and suicide from trials cited by Janssen Cilag to support their application. Three out of the 1,708 trial participants who received Spravato committed suicide. There were no suicides among the 486 subjects who received placebo. (Janssen MD website) The rate of suicidality (suicidal ideation and behaviour) in the group receiving Spravato was double (0.6%) that in the placebo group (0.3%).
In addition, the rate of discontinuation in the trials due to ‘treatment emergent adverse events’ in the placebo group was notably lower. The Spravato group also had a significantly higher incidence of somnolence. (Therapeutic Goods Administration page 31) These are hardly reassuring outcomes for a drug supposed to help people with severe, unremitting depression.
Janssen Cilag is now actively seeking Spravato’s listing on the Pharmaceutical Benefits Scheme. Minister Hunt is retiring from politics after the 21 May 2022 election. Whoever replaces him as the Minister for Health will have the capacity to decide if our taxes are used to subsidise Spravato. Can we trust Minister Hunt's replacement to act exclusively in our interests?
Sadly we can't simply assume that a change of government will prevent similar conflicts of interest. The Liberals coalition partner, the Nationals, and the opposition Labor Party* have also received significant funds from Janssen Cilag and many other pharmaceutical companies.
As I wrote in an earlier PsychWatch Australia blog it would be ideal to ban political donations from pharmaceutical companies and medical device manufacturers, or, failing that, commit to legislating for immediate (real time) public disclosure of all political donations. Unless that occurs questions will remain about the integrity of pharmaceutical regulatory processes.
By Dr Martin Whitely Editor PsychWatch Australia
9 May 2022
*Disclosure: Dr Whitely is a former Labor Member of the Western Australian Parliament and a current ordinary member of the Australian Labor Party. He has no financial conflicts of interest.
REASONS GIVEN FOR THE TGA'S DECISION TO REJECT SPRAVATO'S APPROVAL and FOR THE MINISTER's DECISION TO OVERRULE THE TGA'S DECISION
The TGA’s decided to reject the approval of Spravato because 'there were a number of irresolvable methodological issues with the pivotal efficacy induction trials'. The detailed account of their reasons included the following:
A new antidepressant was initiated at the same time as esketamine, leading to the possibility of confounding. The preference was for only one change to the treatment plan be made at any one time, as otherwise it was directly not straightforward to determine which agent was responsible for the clinical outcomes. An alternative trial design, allowing participants to remain on an existing antidepressant whilst initiating esketamine would have been more appropriate in assessing the efficacy of esketamine, thereby eliminating the current, significant and unacceptable uncertainty associated with the claims of the efficacy of esketamine in patients with TRD.
Separate from the flawed clinical trial design and the failure of two out of the three pivotal studies to reach statistical significance in terms of the primary efficacy outcome, the magnitude of the safety risk management issues to be associated with the use of the product was of concern, in addition to the potential for misuse/diversion of the product.
There was lack of robust data demonstrating exemplary efficacy, probably embedded in the faulty clinical trial.
The reasons given for Minister Hunt's delegate overruling the TGA’s decision were:
Although statistically significant results were achieved in only one of the pivotal induction studies (Study TRD3002), similar effect sizes were seen in the other two studies (Studies TRD3001 and TRD3005).
EDITORIAL COMMENT – Jansenn Cilag were given multiple opportunities to demonstrate efficacy. However, they failed to respond to feedback and address the 'irresolvable methodological issues' identified by the TGA.
In addition, maintenance of antidepressant effect was demonstrated in the relapse prevention study, Study TRD3003.
EDITORIAL COMMENT – The so-called antidepressant effect (improvement in symptoms) in the placebo group was not analysed so there is no way of knowing if Spravto’s use was associated with any beneficial effect.
Adverse events were generally non-serious in nature. Important early adverse effects such as sedation, dissociation, and raised blood pressure can be managed by appropriate post-dose observation.
EDITORIAL COMMENT – Non-serious in nature? All side effects, even the relatively mild effects like nausea, are serious. Mild may have been a better choice of words. Semantics aside, this is a very troubling comment. It completely ignores the higher rates of discontinuation, suicide and suicidality in the Spravota group (compared to the Placebo group). It also trivialises serious concerns about sedation, dissociation and blood pressure.
The clinical evaluator was concerned that the design of the pivotal induction efficacy studies did not allow estimation of the efficacy and safety attributable solely to Spravato. This concern was reflected in the initial decision letter. However, the study design was acceptable to comparable overseas regulators (including the FDA and EMA).
EDITORIAL COMMENT – Why bother having the TGA and the ACM if Ministers are a simply going to cherry-pick decisions they like made by overseas regulators? There are widespread concerns about the regulatory capture of the FDA and other regulators by the pharmaceutical industry. The TGA and the ACM performed a thorough and balanced analysis that in effect Minister Hunt has ignored in favour of a political donor. Throughout the COVID19 pandemic Minister Hunt has repeatedly made comments like''TGA’s processes are I believe the best in the world'. Prime Minister Scott Morrison has made similar statements on multiple occasions. How can they possibly justify overruling the clear decision of what they consider to be the world’s best regulator?
Additionally, the sponsor provided expert opinion that commencing esketamine simultaneously with a new oral antidepressant likely reflected optimal clinical practice.
EDITORIAL COMMENT – An 'expert' chosen by Jansenn Cilag recommended a Jansenn Cilag product. Do we need to say more?
Finally, the Section 60 Delegate accepted that it may be unethical for patients with treatment-resistant depression to be left without any antidepressant treatment (which would be the case in placebo-controlled esketamine monotherapy studies) or on a treatment that has not been sufficiently effective (which would be the case in studies of esketamine together with an existing oral antidepressant).
EDITORIAL COMMENT – Is it ethical for a Minister to ignore the advice of what he describes as the world’s best medical product safety regulator and rely on the advice of an expert chosen by a political donor to approve a treatment produced by the donor?
Democracy for Sale website. Self-generated report created on 29/11/2021 at http://democracyforsale.net/search-aec/ (accessed 28 April 2022)
Janssen MD website. Professional Information Resource. SPRAVATO - Serious Adverse Event - Death. Available at https://www.janssenmd.com/spravato/safety/mortality/spravato-serious-adverse-event-death (accessed 5 May 2022)
Therapeutic Goods Administration. Australian Public Assessment Report for Esketamine hydrochloride Proprietary Product Name: Spravato Sponsor: Janssen-Cilag Pty Ltd. May 2021. Available at https://www.tga.gov.au/sites/default/files/auspar-esketamine-hydrochloride-210507.pdf (accessed 5 May 2022)