Recovery in the Bin published a blog on the 22nd of October highlighting significant ethical concerns about the CALMED Trial, which you can find here.
We contacted both the Health Research Authority (HRA) and the Trial’s Sponsors (Imperial College London) to notify them about our concerns on the 22nd of October.
It is now the 16th of December and the study is continuing to recruit. No study amendments have been submitted to the HRA for approval in response to the concerns we raised.
This means that patients, who would never normally be considered suitable for clozapine, who are not in long-term secure settings, and who have not received psychological therapies in the first instance, are being prescribed clozapine at a lower ‘last resort’ threshold than recommended by NICE and the BNF for Schizophrenia.
We publish here, for transparency, the responses received so far from Imperial College London and the HRA. We conclude with a call to ACTION.
Trial Sponsors: Imperial College London
Trial Sponsors are the primary organisation responsible for a study – every study will have a ‘Sponsor’. The CALMED Trial is sponsored by Imperial College London and we contacted their Office for Research Integrity, who were listed as the Sponsor contact.
We notified Imperial College of our concerns on the 22nd of October. We received a confirmation email that our concerns would be investigated.
We heard nothing.
We contacted Imperial College on the 10th of December for an update:
“Dear CALMED Trail Sponsors,
We notified you on the 22nd of October about our concerns regarding the CALMED Trial. We have not heard anything since, other than an acknowledgement that you are investigating our concerns.
We are now emailing to request an update about what actions you have taken in response to our concerns and the outcome of any action you have taken.
We look forwards to hearing from you,
We received this response on the 16th of December:-
Thank you for getting in contact, the concerns raised have been investigated and further engagement undertaken with patients and the public, updates of this will be presented in March at the national personality disorder conference. An amendment to the study will also be submitted to provide further clarification on the inclusion criteria of the study.
We responded to this email on the 16th of December:
Thank you for your email.
As requested in our initial email, and for transparency, please could you provide us with an account of all the actions you or the research team have taken to address our concerns. This includes how our concerns were addressed through your complaints procedures and Standard Operating Procedures.
It is not acceptable for us to wait until a conference in March to hear the outcome of your investigation.
We are concerned that an amendment has not yet been submitted. Please could you inform us why there has been a delay?
We are extremely concerned that an amendment to protect participants has not yet been submitted to the HRA for approval after 2 months.
Health Research Authority (HRA)
The Health Research Authority is the overall organisation that oversees ethical approval for studies that recruit patients through the NHS. The CALMED Trial was approved by a HRA Research Ethics Committee.
We notified the HRA about our concerns on the 22nd of October. We received a confirmation email on the 23rd of October to state that our concerns had been received were being investigated in line with their Third Party Concerns Procedures. We were told that it would take 25 working days to investigate and the reasons for any delay beyond 25 working days would be explained to us.
On the 27th of November (the 25th working day) we received the following email:
I advised you in my email dated 23 October 2019 that we would provide you with an update on progress today. We are continuing to work on this investigation, and will be in touch with you again within the next two weeks.
We responded on the 27th of November to request further information about why there was a delay.
Thank you for getting in touch.
In your email dated the 23rd of October you stated that: ‘Where the investigation cannot be completed within 25 working days we will keep you informed about the reasons for the delay and the expected timescale for completion.’
Could you let us know the reasons for the delay?
Also we would very much appreciate some information about what actions have been taken to address the concerns we raised. We are concerned about patient safety and we have already waited 25 working days and have not received reassurance that something is being done to protect vulnerable participants.
On the 28th of November we received this response:
Thank you for your email of 27 November.
The issues you raised about the CALMED study are being investigated in line with our standard process for Third Party Concerns.
This process includes establishing which of the issues raised with us are within the remit of the Health Research Authority. Once we have done this, we identify senior staff who were not involved in the original study review. These staff collate relevant documentation and review the study in light of the concerns raised to decide on any action that needs to be taken. In some cases this may include a review of the original ethics opinion.
This process can be time consuming. The CALMED study was reviewed by a Research Ethics Committee in Wales and we are working with our colleagues at Health and Care Research Wales (HCRW) to ensure that we have all necessary documentation to consider the concerns you have raised with us. We expect to have completed our investigation within the next two weeks and will write to you again when we have done so.
It is important to point out that whilst in some exceptional cases the HRA can withdraw the ethical approval of a study which is in progress, it does not have the power to halt a study when concerns are raised. Please be advised the Medicines & Healthcare products Regulatory Agency (MHRA) has the primary responsibility for the safety of medicinal trials. Under the Clinical Trials Regulations, the decision to suspend or terminate the Clinical Trials Authorisation and therefore to halt a trial lies solely with the MHRA.
On the 10th of December we contacted the HRA to obtain an update as we had not heard within the 2 weeks time frame.
We are emailing to get an update about the progress of the investigation. If you could let us know the current stage of the investigation that would be great. We have waited now for nearly 2 months, which is an awfully long time given the significant concerns we have raised.
On the 12th of December we received this response:
My apologies for the delay. I am meeting with the individual investigating your concern tomorrow and will provide an update after this meeting.”
At the time of publication (16.12.19) we have not had a response from the HRA.
A call for action
2 months have passed since we blogged about our significant concerns about patient safety. 2 months ago we notified the Trial Sponsors and the HRA of these concerns.
After 2 months, we have not received information about what actions both the HRA and the Trial Sponsors have taken to address the concerns raised in our blog. The trial sponsors have not yet submitted an amendment for approval to protect patient safety – this is unacceptable.
We have been patient – we have waited 2 months. We will not be patient any longer – patient safety is at stake.
Current systems available to the public to raise concerns about studies are woefully inadequate. They do not act in a timely manner to protect patient safety and they are not sufficiently transparent.
Accountability can be deferred to other organisations and approving bodies, for example to the MHRA by the HRA, or to the HRA by the Trial Sponsors. This makes it very difficult for any concerns about studies to be addressed quickly.
We strongly urge our allies to support our campaign for a swift and transparent resolution to our concerns about the CLAMED Trial. We are a grassroots service user group and do not have paid members of staff. We do what we can.
If you have influence, we urge you to use this so our concerns can be addressed swiftly and transparently.
- Sign and share a Change petition that we have created HERE
- Contact the HRA and express your concerns to Stephen Tebutt, Head of Corporate Governance and Risk, quoting the reference 19.TP.09: email@example.com
- Contact the Trial Sponsor (Imperial College) and express your concerns to Ruth Nicholson, Head of Research Governance and Integrity: firstname.lastname@example.org
- Contact the MHRA (Clinical Trial Regulators): Jennifer.Martin@mhra.gov.uk. Reference: GCEP-00140808.
- Contact the NIHR (Funders): Stephanie Garfield-Birkbeck: email@example.com
We cannot do this alone.
We are not prepared to wait for a conference in March 2020 to hear what action has been taken.
UPDATES: 17.12.19 & 23.12.19
- Trial Sponsors: Imperial College Updates
We are yet to recieve an answer to the questions we asked Imperial College. We have recieved no further correspondence from anyone at Imperial College since our blog was published.
- Medicines and Healthcare products Regulatory Agency (MHRA) Updates
We notified the MHRA of our concerns relating to the CALMED Trial on the 16.12.2019, which also included the way in which our concerns have been addressed to date. The MHRA regulate clinical trials which involve medication.
On the 20.12.2019 we recieved the following response, notifying us that an amendment to the trial had been expidited and approved by the MHRA. No further details pertaining to the amendment were provided. They notified us that they are conducting their own review into the study.
Thank you for your email of 19th December.We are aware of the CALMED trial and are conducting a review. MHRA has received an amendment to update the protocol and this has been expedited and approved. An initial review of safety undertaken at the same time has not highlighted any significant concerns that would require us to take urgent regulatory action. Patients are appropriately monitored and all patients are treated in the trial on top of standard of care interventions, including psychological interventions and occupational activities.
- National Institute for Health Research (NIHR) Updates
We notified the NIHR of our concerns relating to the CALMED Trial on the 16.12.2019, which also included the way in which our concerns have been addressed to date. The NIHR funded the CALMED Trial and wrote the commissioning brief for a RCT to investigate the effetiveness of clozapine for BPD.
On the 19.12.19 we recieved the following response:
Thank you for your email which I acknowledge. Your request to investigate your concerns has been noted. In the meantime please note we will not be able to comment on investigations by other organisations. Yours sincerely
We received the following email from the HRA on the 17th of December:
I have now spoken with the individual investigating your concern who has advised the research team is in discussions with the funder regarding making an amendment to the study. We anticipate confirmation shortly and will provide an update as soon as possible.
We responded on the 17th of December at 11:50am:
Thank you for letting us know.
Could you let us know if your investigation has concluded that the original ethics decision requires amending or withdrawing?
We responded again at 4:07pm:
Could you let us know when we will receive your answer to our question?
We are concerned that we are not being provided with all information relating to the investigation in a transparent and timely manner.
Our complaint was submitted to the HRA (not the study team), in order to ensure that an impartial review of the original REC approval was conducted. We therefore expect to hear how this REC decision has been impartially appraised by the HRA as an independent body in light of our concerns. We also expect to hear what actions you will be recommending through the HRA and timescales for these actions.
Negotiations with the study team and discussions about a future amendment with the study team are not a substitute for an impartial, independent review by the HRA regarding the original REC approval.
We have notified the MHRA and NIHR of our concerns about the trial today.
We received an update report from the HRA on the 22.12.2019. This is a 3 page document which consists of a number of quotes from the HRA’s Standard Operating Procedures. It is too lengthy to include here in full, but you can access it here. They notified us that an amendement was submitted to the HRA (REC) and MHRA on the 17th of December, (this blog was originally published on the 16th). In their report they state that this amendment relates to specifying BPD severity.
“HRA can confirm that an amendment was submitted on 17 December to both the REC and MHRA. NIHR have confirmed that at the end of November 13 participants had been recruited.
The HRA has approached MHRA who have the expertise and responsibility for reviewing the safety of the study. Following a number of exchanges, MHRA have noted that the patient population is restricted to inpatients and therefore the study population would be limited to patients with sever[e] Border[line] Personality Disorder. However, they note that the protocol was not explicit in relation to severity, and that less severe patients could have been included. The new amendment is therefore regarded by MHRA as a clarification.”
On the 22.12.19 we provided an initial response to the HRA, it can viewed in full here. We will work with our allies to draft a complete response in the New Year – if you would like to assist with this, please contact us at firstname.lastname@example.org.
In our initial response we welcomed an amendment to ensure BPD severity is an inclusion / exclusion criteria (pending further information about how this will be assessed). However, we highlighted that many of the concerns raised in our initial blog had not been addressed. We asked the HRA two questions in our initial response which need answering at the earliest opportunity:
QUESTION ONE: Why is Clozapine being prescribed in this study at a lower ‘last resort’ threshold than the BNF and NICE recommend for treatment resistant Schizophrenia (the only mental health condition which Clozapine is licensed for in the UK)?
QUESTION TWO: Why is a failure to respond to, or decline, NICE recommended therapies for BPD not included as an inclusion / exclusion criteria?
Our response to the HRA was sent to the Trial Sponsor’s, NIHR and MHRA, to enable them to respond within their own remits.