Are Regulatory Bodies Prioritising Drug Company Interests Over Public Safety?

The Disturbing Case of the Street Drug Ketamine

The UK’s Medicines & Healthcare Products Regulatory Agency [MHRA] is refusing to respond to the concerns of psychiatrists, parliamentarians, patients and other experts about the impending licensing of the street drug ketamine as a treatment for depression.

In March this year, the USA’s Food and Drug Administration approved Spravato (esketamine), on the basis of just one efficacy study.

On 17.10.19 the European Medicines Agency [EMA] issued a ‘positive opinion’ recommending the granting of marketing authorisation for esketamine for depression in adults and sent it to the European Commission, which has 67 days to make a final decision (December 23).

The MHRA (UK) has deferred a decision, pending the EMA/EC ruling. However, during the 67 days, member states can submit new information not addressed by the EMA opinion.

On 31.10.19 twelve experts, including eight psychiatrists, wrote to the MHRA and EMA.

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Dr June Raine
Chief Executive Officer
Medicines & Healthcare Products Regulatory Agency
London E14 4PU

October 31, 2019

Dear Dr Raine

We are writing to express grave concern about the possibility that the dissociative anaesthetic agent, and known street drug of abuse, ketamine, might be approved for use in this country in the marketed form of ‘esketamine’.

There have been no trials of the efficacy of esketamine in the medium or long term. The majority of the studies of this drug (almost entirely conducted by the drug company attempting to license the drug, Janssen) are only four weeks in duration. Most of these studies find no benefit for esketamine versus placebo, and multiple adverse effects. The one positive efficacy study finds a difference between esketamine and placebo that is small and not clinically meaningful.  Esketamine is the only antidepressant that has been approved by the FDA with only one successful efficacy trial.

The longest study to date is a 16 week trial using a discontinuation design, which is almost certain to confound withdrawal effects with relapse of depression. This trial design also increases the likelihood of patients breaking blind in the drug condition.  As noted in the FDA statistical review, “perception of their treatment assignment may have been influenced by acute side effects (dissociation, sedation, etc.). FDA’s exploratory analysis suggested that changes in these side effects were associated with time relapse.”

Notably, there were six deaths in the esketamine studies, including three suicides, all in the esketamine group, with none in those assigned to placebo. Although these deaths were dismissed as unrelated by Janssen we do not believe that this worrying signal of danger should be ignored. It may well be consistent with a severe withdrawal reaction from the medication, known to occur in other medications such as antidepressants and opiates.

Short term apparent benefits of using esketamine are unsurprising, given its similarities to drugs of abuse, and no basis for approving a drug. One could achieve similar results, short term euphoria or dissociation, with various other street drugs. Indeed, we are as shocked by this recent development as we would have been had es-cocaine been submitted for approval.

If esketamine is approved for public use in the UK next month, there is no impediment to doctors prescribing this drug for weeks, months and beyond, which is precisely what we now see occurring in the US since FDA approval.

We trust that an evidence-based approach will be taken to your decision and, therefore, that no approval will be granted until multiple independent trials (i.e. not industry-sponsored) of at least a year, and preferably longer, have been conducted.

Yours

Dr John Read, Professor of Clinical Psychology, University of East London.
Dr Pat Bracken, Consultant Psychiatrist, Ireland
Dr James Davies, Medical Anthropology, University of Roehampton
Dr Peter J Gordon, Consultant Psychiatrist for Older Adults, NHS West Lothian.
Dr Rex Haigh, Consultant Psychiatrist in Medical Psychotherapy, Berkshire NHS
Dr Peter Kinderman, Professor of Clinical Psychology, University of Liverpool
Dr Irving Kirsch, Associate Director, Program in Placebo Studies, Harvard Medical School;
Professor Emeritus, Psychology: University of Connecticut (USA) & University of Hull (UK)
Dr Hugh Middleton, Psychiatrist, University of Nottingham
Dr Clive Sherlock, Psychiatrist, Oxford
Dr Derek Summerfield, Consultant Psychiatrist; Hon. Senior Clinical Lecturer – Institute of Psychiatry, Psychology & Neuroscience, King’s College, London
Dr Philip Thomas, Formerly Professor of Philosophy, Diversity & Mental Health, University of Central Lancashire; Formerly Consultant Psychiatrist
Dr Sami Timimi, Consultant Child and Adolescent Psychiatrist

***

Despite many subsequent emails, no meaningful response to the concerns raised, and research evidence provided, has been received from the MHRA. Efforts, with both the MHRA and the EMA, to obtain minutes of meetings, committee memberships and conflict of interest statements of individuals involved in esketamine decisions, have failed.

On 29.11.2019, the twelve wrote to the MHRA again, saying:

‘It is incumbent upon the MHRA to exercise their obligation, within the permitted 67 day period, to raise the various safety and efficacy issues clearly not dealt with in the EMA ‘opinion’ and insist that the procedure be referred back for further examination. We believe that failure to do this would represent a blatant failure to fulfil its remit to act in the public health interest of the citizens of the UK.’

No meaningful response has been received.

The MHRA has also failed to respond to multiple letters from the All-Party Parliamentary Group (APPG) for Prescribed Drug Dependence asking when MHRA would be discussing the drug. In October, the APPG’s chair, Sir Oliver Letwin MP, wrote to the UK regulator outlining his objections to esketamine as a drug likely to cause ‘dependence, addiction and withdrawal’. He asked MHRA not to approve esketamine, ‘at least until long-term trials have taken place and the long-term risks are fully understood’.

Members of the UK online support group, Let’s Talk Withdrawal, which represents people negatively affected by antidepressants, antipsychotics and benzodiazepines, also wrote to the MHRA requesting longer-term studies before esketamine is licensed. Their letter was not even acknowledged.

In October, the evidence for esketamine was scathingly critiqued in the Lancet, by prominent U.S. psychiatrist Dr Erick Turner (a member of the USA’s Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee).

The role of drug companies

In the U.S. it costs more than £25,000 ($33,000) to treat one patient for a year with esketamine.

The lack of transparency of these agencies is a serious matter. If they approve esketamine, on the basis of such inadequate research, it will suggest they are more interested in keeping the drug company happy than keeping the public safe.

89% of the EMA’s funding, and 100% of the MHRA’s funding, comes from drug company fees.

Both the members sent by MHRA to represent the UK on the EMA, Dr Nithyanandan Nagercoil and Dr Marie-Christine Bielsky, are ex-employees of drug companies.

The two most prominent promoters of esketamine in the UK, psychiatrists Professor Allan Young and Dr Rupert McShane, both have significant financial links with Janssen-Cilag, the maker of esketamine.

Consultant Psychiatrist, Dr Rex Haigh, a co-signatory to the 31.10 letter, commented:

‘The evidence is that ketamine is the most dangerous of the psychedelics and dissociants. We remain hopeful that unlike the USA’s FDA, our MHRA will take an evidence-based approach, ignore the drug company hype, and decline the application’

Professor Peter Kinderman (Liverpool University), another co-signatory, added:

‘This drug has been widely criminalised to protect people from the harms associated with it. While we certainly need new ways of helping people in distress, prescribing party drugs is unlikely to be the answer.’

Another co-signatory, Dr James Davies, a spokesman for the Council for Evidence-Based Psychiatry has stated:

‘We are deeply concerned about the proposed approval of esketamine. It works via an opioid mechanism and is likely to cause serious problems of addiction and withdrawal.

‘No one should forget the troubled history of psychiatric medication, where supposedly safe and effective medicines turn out to be addictive and damaging when used long term. We urge the MHRA to deny this drug a licence at least until long-term trials on safety and efficacy have been completed.’