Daisymay
Senior Member
- Messages
- 754
This is being sent on behalf of Professor Malcolm Hooper. Permission to repost.
Medical Research Council
Professor Malcolm Hooper,
2 Nursery Close,
Sunderland
SR3 1PA
23 February 201121 February 2011
Dear Professor Hooper,
I am writing in response to your letter of 26th January. I am sorry you found my earlier letter in response to your complaint about the PACE trial disappointing. It appears that my letter, which I sent to your University address, took some time to reach you. I did send it also by e-mail, but I note that you have changed your e-mail address.
Many of your concerns relate to the aetiology and disease mechanisms of CFS/ME, the disease classification and the diagnostic criteria used, and I cannot comment much further on these issues - the MRC acknowledges that CFS/ME is a distressing and debilitating condition and that not enough is known about the aetiology and mechanisms involved. To help address this we have recently announced the allocation of 1.5m for a call for proposals to encourage more research, focussing on the priority areas identified by the expert group last year, namely:
.Autonomic dysfunction
.Cognitive symptoms
.Fatigue
.Immune dysregulation (eg. through viral infection)
.Pain
.Sleep disorders
Details are on our web site at www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm#P80_5718
In deciding to fund the PACE trial, the MRC relied (as it does for any such funding decision) on peer review by clinical and scientific experts in the field, and by experts in the design and conduct of clinical trials. These experts, and the experts on the Research Ethics Committees that approved the trial, were satisfied with the protocol, which lays out the entry criteria and outcome measures to be used. You clearly fundamentally disagree with these experts, but it is not appropriate for MRC officials to enter into this scientific debate, which is best conducted in the scientific literature. As clearly stated in the protocol, which as you know was published in the open access journal BioMed Central Neurology in 2007, the aim of the PACE trial was to provide evidence about the relative benefits, cost effectiveness and adverse effects of the most widely advocated treatments for CFS/ME. The validity of the trial does not depend on any particular theory of disease aetiology or causation; it was simply designed to show whether the treatments in common use are safe and effective. The trial is now complete and the results have been published in The Lancet www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60172-4/abstract.
You have highlighted specific issues in your lengthy document to which you felt I had not adequately responded, and I will provide what additional responses I can in the order of your numbered paragraphs.
1. In your view the entry criteria used mean that the PACE trial is studying patients who have chronic fatigue and not CFS/ME, and you are concerned that the results might be applied to different patient groups. The clinical and scientific experts who reviewed the protocol were satisfied with the entry criteria, which are clear in the published protocol and are also set out clearly in the published results, so that clinicians and others using the results of the trial to inform their practice will know which patient groups the treatments should be applied to.
2. You state that participants in a clinical trial should not be told how effective the intervention they are receiving is. However, in order that properly informed consent can be obtained, it is normally considered important that participants are told any information that is known about the likely effectiveness (and possible harms) of the treatments being trialled. You express a concern that the motivation for publishing positive comments from participants in the trial newsletter, and encouraging them to let other sufferers know about the trial, was to influence the outcome; I am not in a position to comment on the triallists motivation, but it seems unlikely that reading such comments, which did not mention specific treatments, would have a material effect on participants health and we do not consider it unethical to publish comments from current participants in order to encourage interest in the trial. All participant newsletters circulated during the trial were considered ethically satisfactory by the MREC before being sent out.
3. As noted above, I cannot comment on the use of particular diagnostic criteria. The independent members of the trial steering committee reviewed and agreed the plans for secondary analysis and those that are to be published will have been reviewed by the expert peer reviewers selected by the journal.
4. I acknowledge that there have been changes to the protocol for the PACE trial since it started. It is not uncommon for minor protocol modifications to be made while a trial is in progress; all such modifications must be approved by the Trial Steering Committee (TSC), the Data Monitoring and Ethics Committee, and the MREC that approved the original protocol, and they were in this case. In addition, the MRC Board was aware of the changes when it agreed to the extension to the original funding period for the trial, so clearly the Board did not consider the changes undermined the trial.
5. The peer reviewers and the MRC Board were satisfied that the PACE trial was adequately justified based on the extant literature when the funding decision was taken. The published protocol refers to two independent systematic reviews of treatment for CFS/ME. In addition, the TSC monitored any new findings emerging in the scientific literature during the course of the trial which could potentially have an impact on the design or rationale for the trial; had any such findings meant that the trial was no longer ethically or scientifically justified then the TSC would have stopped the trial.
6. Neither the patient clinic leaflet nor the PACE trial invitation letter (which provided information on the trial to potential participants), portray CFS/ME as a dysfunctional belief. The clinic leaflet gives information on several possibilities as to the causes of the condition, including infections, immune and hormonal factors.
7. The information given to patients makes it clear that doctors would rule out other physical diseases before diagnosing CFS/ME or offering entry into the PACE trial, but also explains various abnormalities found in patients with a diagnosis of CFS/ME. There is no statement or implication that that there is no physical disease; the patient clinic leaflet says on the front page In this clinic we believe CFS/ME is a real illness.
8. You are correct, cardiovascular and immunological screening were not included in the protocol for the pre-trial assessment. However, as mentioned above, doctors carried out a range of medical tests in order to diagnose CFS/ME and rule out other possible causes of the symptoms before patients were offered entry into the trial. These tests included a physical examination and several tests of the immune system.
9, 10 & 11. All these points relate to the outcome measures for the trial. These were judged to be appropriate by the expert clinical and scientific reviewers and by the MREC which approved the protocol; any changes to the original protocol would have had to be approved by the MREC and the TSC.
12. The MRC considers that the views of the principal investigators as to the nature of the disease or the potential mechanism of action of the interventions being tested, or whether these are revealed to potential trial participants, have no bearing on participants ability to give informed consent.
13. The PACE trial treatment manuals were reviewed by the MREC which approved the trial.
14. In a clinical trial, the requirement for equipoise relates to the evidence as to the efficacy or effectiveness (in absolute terms and relative to each other) of the interventions under trial, and not to the beliefs of the investigators (or anyone else) regarding the causes of the disease.
15. At the first meeting of a new Trial Steering Committee, the focus is usually on establishing that the independent members, involved with the trial for the first time, have any conflicts to declare, which was the case in this trial. The Principal Investigators are automatically assumed to have conflicts arising from their role, which is why independent members and an independent chair are required for the TSC. In relation to financial conflicts, the PACE PIs have repeatedly declared the potential conflicts arising from their having had consultancies with the DWP or insurance companies. The MRC, and the Research Ethics Committees, took the view that these links did not compromise their ability to run the trial. In order to avoid bias in the results, the statistician who analysed the main trial data was blinded as to the treatment allocation of the four groups of patients.
I cannot comment on the NICE guidance; any concerns regarding the development of this guidance should be taken up with NICE directly.
You ask why questions relating to the participants financial situation were included in the pre-trial assessment. We accept that this is unusual in a clinical trial but, as is clear from the published protocol, being in receipt of a disability pension was amongst a group of factors found in previous work to be potential predictors of a negative response to treatment. The inclusion of financial questions was therefore made part of the investigation into predictors of outcome. The other reason to include financial questions was to be able to measure how treatments affected both healthcare costs and costs to society. It was made clear in the patient invitation letter prior to recruitment that such questions were included, so that patients not willing to answer could decline to participate.
The MRC does not believe that the beliefs regarding the aetiology of CFS/ME materially affect the ability of members of the Data Monitoring and Ethics Committee to act independently, since data provided to the DMEC were blinded as to treatment allocation.
I acknowledge that there was unfortunately one instance of a breach of security during the PACE trial, when one recording containing confidential patient information was stolen from within a hospital, having not been kept sufficiently secure. Security procedures were changed after this incidence and we are not aware of any further problems.
You allege that the MRC Neurosciences and Mental Health Board (NMHB) has behaved in a biased fashion and has been controlled by psychiatrists in their funding decisions regarding applications for research into CFS/ME. I cannot provide specific evidence to prove otherwise, since Board discussions are confidential. However, all the MRC Boards take collective responsibility for their funding decisions, all members take an active part in decision-making, all members are required to act according to the seven principles of public life (the Nolan principles), and the Board Secretary (a member of MRC office staff) and the Chair are required to ensure that decision-making processes are fair. The membership of NMHB covers the full range of expertise in neuroscience and mental health, and only a small proportion of members are psychiatrists at any one time, so it is unlikely they could control the outcome of decisions. It is true to say that the many applicants whose applications are declined (around 80%) are rarely happy with the decision, whatever the Board or panel involved, and some would rather believe that the process is flawed than accept that their application did not reach the competitive standard. Some revise their applications taking into account the comments from peer reviewers and the Board and are subsequently successful in obtaining funding from MRC or another funding body.
I have responded as fully as I can to your concerns. However, it is clear that many of the points on which you consider my earlier response inadequate relate to scientific disagreements on which I cannot comment further.
If you are not satisfied with how I have handled your complaint, you may choose to refer it to the MRC Complaints Officer, in accordance with stage 2 of MRCs formal complaints procedure, detailed on our web site at
www.mrc.ac.uk/About/Informationandstandards/Complaints/index.htm. Please note, however, that the complaints procedure specifically excludes complaints which amount to a disagreement with the scientific decisions made by MRC Boards, Panels and other Committees. I should point out that since the Complaints Officer is a member of my team within Head Office, she would necessarily refer any formal complaint to another senior member of staff in a different department.
Yours sincerely
Frances C Rawle PhD
Head of Corporate Governance and Policy
direct line: 0207 395 2285
email: frances.rawle@headoffice.mrc.ac.uk
Medical Research Council
Professor Malcolm Hooper,
2 Nursery Close,
Sunderland
SR3 1PA
23 February 201121 February 2011
Dear Professor Hooper,
I am writing in response to your letter of 26th January. I am sorry you found my earlier letter in response to your complaint about the PACE trial disappointing. It appears that my letter, which I sent to your University address, took some time to reach you. I did send it also by e-mail, but I note that you have changed your e-mail address.
Many of your concerns relate to the aetiology and disease mechanisms of CFS/ME, the disease classification and the diagnostic criteria used, and I cannot comment much further on these issues - the MRC acknowledges that CFS/ME is a distressing and debilitating condition and that not enough is known about the aetiology and mechanisms involved. To help address this we have recently announced the allocation of 1.5m for a call for proposals to encourage more research, focussing on the priority areas identified by the expert group last year, namely:
.Autonomic dysfunction
.Cognitive symptoms
.Fatigue
.Immune dysregulation (eg. through viral infection)
.Pain
.Sleep disorders
Details are on our web site at www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm#P80_5718
In deciding to fund the PACE trial, the MRC relied (as it does for any such funding decision) on peer review by clinical and scientific experts in the field, and by experts in the design and conduct of clinical trials. These experts, and the experts on the Research Ethics Committees that approved the trial, were satisfied with the protocol, which lays out the entry criteria and outcome measures to be used. You clearly fundamentally disagree with these experts, but it is not appropriate for MRC officials to enter into this scientific debate, which is best conducted in the scientific literature. As clearly stated in the protocol, which as you know was published in the open access journal BioMed Central Neurology in 2007, the aim of the PACE trial was to provide evidence about the relative benefits, cost effectiveness and adverse effects of the most widely advocated treatments for CFS/ME. The validity of the trial does not depend on any particular theory of disease aetiology or causation; it was simply designed to show whether the treatments in common use are safe and effective. The trial is now complete and the results have been published in The Lancet www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60172-4/abstract.
You have highlighted specific issues in your lengthy document to which you felt I had not adequately responded, and I will provide what additional responses I can in the order of your numbered paragraphs.
1. In your view the entry criteria used mean that the PACE trial is studying patients who have chronic fatigue and not CFS/ME, and you are concerned that the results might be applied to different patient groups. The clinical and scientific experts who reviewed the protocol were satisfied with the entry criteria, which are clear in the published protocol and are also set out clearly in the published results, so that clinicians and others using the results of the trial to inform their practice will know which patient groups the treatments should be applied to.
2. You state that participants in a clinical trial should not be told how effective the intervention they are receiving is. However, in order that properly informed consent can be obtained, it is normally considered important that participants are told any information that is known about the likely effectiveness (and possible harms) of the treatments being trialled. You express a concern that the motivation for publishing positive comments from participants in the trial newsletter, and encouraging them to let other sufferers know about the trial, was to influence the outcome; I am not in a position to comment on the triallists motivation, but it seems unlikely that reading such comments, which did not mention specific treatments, would have a material effect on participants health and we do not consider it unethical to publish comments from current participants in order to encourage interest in the trial. All participant newsletters circulated during the trial were considered ethically satisfactory by the MREC before being sent out.
3. As noted above, I cannot comment on the use of particular diagnostic criteria. The independent members of the trial steering committee reviewed and agreed the plans for secondary analysis and those that are to be published will have been reviewed by the expert peer reviewers selected by the journal.
4. I acknowledge that there have been changes to the protocol for the PACE trial since it started. It is not uncommon for minor protocol modifications to be made while a trial is in progress; all such modifications must be approved by the Trial Steering Committee (TSC), the Data Monitoring and Ethics Committee, and the MREC that approved the original protocol, and they were in this case. In addition, the MRC Board was aware of the changes when it agreed to the extension to the original funding period for the trial, so clearly the Board did not consider the changes undermined the trial.
5. The peer reviewers and the MRC Board were satisfied that the PACE trial was adequately justified based on the extant literature when the funding decision was taken. The published protocol refers to two independent systematic reviews of treatment for CFS/ME. In addition, the TSC monitored any new findings emerging in the scientific literature during the course of the trial which could potentially have an impact on the design or rationale for the trial; had any such findings meant that the trial was no longer ethically or scientifically justified then the TSC would have stopped the trial.
6. Neither the patient clinic leaflet nor the PACE trial invitation letter (which provided information on the trial to potential participants), portray CFS/ME as a dysfunctional belief. The clinic leaflet gives information on several possibilities as to the causes of the condition, including infections, immune and hormonal factors.
7. The information given to patients makes it clear that doctors would rule out other physical diseases before diagnosing CFS/ME or offering entry into the PACE trial, but also explains various abnormalities found in patients with a diagnosis of CFS/ME. There is no statement or implication that that there is no physical disease; the patient clinic leaflet says on the front page In this clinic we believe CFS/ME is a real illness.
8. You are correct, cardiovascular and immunological screening were not included in the protocol for the pre-trial assessment. However, as mentioned above, doctors carried out a range of medical tests in order to diagnose CFS/ME and rule out other possible causes of the symptoms before patients were offered entry into the trial. These tests included a physical examination and several tests of the immune system.
9, 10 & 11. All these points relate to the outcome measures for the trial. These were judged to be appropriate by the expert clinical and scientific reviewers and by the MREC which approved the protocol; any changes to the original protocol would have had to be approved by the MREC and the TSC.
12. The MRC considers that the views of the principal investigators as to the nature of the disease or the potential mechanism of action of the interventions being tested, or whether these are revealed to potential trial participants, have no bearing on participants ability to give informed consent.
13. The PACE trial treatment manuals were reviewed by the MREC which approved the trial.
14. In a clinical trial, the requirement for equipoise relates to the evidence as to the efficacy or effectiveness (in absolute terms and relative to each other) of the interventions under trial, and not to the beliefs of the investigators (or anyone else) regarding the causes of the disease.
15. At the first meeting of a new Trial Steering Committee, the focus is usually on establishing that the independent members, involved with the trial for the first time, have any conflicts to declare, which was the case in this trial. The Principal Investigators are automatically assumed to have conflicts arising from their role, which is why independent members and an independent chair are required for the TSC. In relation to financial conflicts, the PACE PIs have repeatedly declared the potential conflicts arising from their having had consultancies with the DWP or insurance companies. The MRC, and the Research Ethics Committees, took the view that these links did not compromise their ability to run the trial. In order to avoid bias in the results, the statistician who analysed the main trial data was blinded as to the treatment allocation of the four groups of patients.
I cannot comment on the NICE guidance; any concerns regarding the development of this guidance should be taken up with NICE directly.
You ask why questions relating to the participants financial situation were included in the pre-trial assessment. We accept that this is unusual in a clinical trial but, as is clear from the published protocol, being in receipt of a disability pension was amongst a group of factors found in previous work to be potential predictors of a negative response to treatment. The inclusion of financial questions was therefore made part of the investigation into predictors of outcome. The other reason to include financial questions was to be able to measure how treatments affected both healthcare costs and costs to society. It was made clear in the patient invitation letter prior to recruitment that such questions were included, so that patients not willing to answer could decline to participate.
The MRC does not believe that the beliefs regarding the aetiology of CFS/ME materially affect the ability of members of the Data Monitoring and Ethics Committee to act independently, since data provided to the DMEC were blinded as to treatment allocation.
I acknowledge that there was unfortunately one instance of a breach of security during the PACE trial, when one recording containing confidential patient information was stolen from within a hospital, having not been kept sufficiently secure. Security procedures were changed after this incidence and we are not aware of any further problems.
You allege that the MRC Neurosciences and Mental Health Board (NMHB) has behaved in a biased fashion and has been controlled by psychiatrists in their funding decisions regarding applications for research into CFS/ME. I cannot provide specific evidence to prove otherwise, since Board discussions are confidential. However, all the MRC Boards take collective responsibility for their funding decisions, all members take an active part in decision-making, all members are required to act according to the seven principles of public life (the Nolan principles), and the Board Secretary (a member of MRC office staff) and the Chair are required to ensure that decision-making processes are fair. The membership of NMHB covers the full range of expertise in neuroscience and mental health, and only a small proportion of members are psychiatrists at any one time, so it is unlikely they could control the outcome of decisions. It is true to say that the many applicants whose applications are declined (around 80%) are rarely happy with the decision, whatever the Board or panel involved, and some would rather believe that the process is flawed than accept that their application did not reach the competitive standard. Some revise their applications taking into account the comments from peer reviewers and the Board and are subsequently successful in obtaining funding from MRC or another funding body.
I have responded as fully as I can to your concerns. However, it is clear that many of the points on which you consider my earlier response inadequate relate to scientific disagreements on which I cannot comment further.
If you are not satisfied with how I have handled your complaint, you may choose to refer it to the MRC Complaints Officer, in accordance with stage 2 of MRCs formal complaints procedure, detailed on our web site at
www.mrc.ac.uk/About/Informationandstandards/Complaints/index.htm. Please note, however, that the complaints procedure specifically excludes complaints which amount to a disagreement with the scientific decisions made by MRC Boards, Panels and other Committees. I should point out that since the Complaints Officer is a member of my team within Head Office, she would necessarily refer any formal complaint to another senior member of staff in a different department.
Yours sincerely
Frances C Rawle PhD
Head of Corporate Governance and Policy
direct line: 0207 395 2285
email: frances.rawle@headoffice.mrc.ac.uk
