Amendment 2.2 Cover letter - 24/11/2004 Substantial amendment form ~ 24/11/2004 REC acknowledgement letter — 03/12/2004 REC opinion letter - 15/12/2004. ace Poce Thal Centre, Std Hoor, Dominion Hause, St Bartholomew's Hospital, London ECIA 7BE Yelephone 020 7601 8160 Facsimile: 020 7490 579} Emali: paceegmulcc.ut Mrs Anne McCullough Administrator, West Midlands Multi-centre Research Ethics Committee 27 Highfield Road, Be RECEIVED 25N¥ Doh B15 3DP 24" November 2004 Dear Ms McCullough, Full title of study: The PACE trial — A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist modical caro versus standardised specialist medical care alone for patients with the chronic fatigue syndrome / myelgic encephalomyelitis or encephalopathy MREC reference number 02/7/89 We are grateful for the opinion of the Research Ethics Committee sub- committee, from the meeting held on the 25” October 2004, regarding amendment 2.1, dated 22” October 2004. We are pleased to respond to these suggestions below. 4. The two stage consent procedure The excerpt from your letter reads as follows “The members were unable to understand the need for a two stage consent procedure. It is typical of many studies that the subject’s consent to the ‘study is obtained prior to eligibility screening — which might the fine them to be ineligible. This is appropriate since it ensures that no trial-related procedures are performed without consent. They did not feel that you had adequately justified a more complex procedure and consent and do not believe that the second stage consent form adds anything to the consent obtained at the first stage.” bcc] : CP age DWP Berta Posing, gtoded Activty and Cognltve behoviou!Iherapr@ randomized valuation PACE ie Mad Clee: 3 Float Demin Howse St Bertnslameu/ Hostal Lencon ECIA 7 Tl 9207401 8140 Fax £29760 $90) malt peseterl act The PACE id irda y the ics Rnaoth CouncREG: 22 Nevemter 2008 205 IsReTNSazes056 We both acknowiedge and apologise for the fact that we did not adequately explain our reasoning behind the two stage consent procedure, and we are pleased to have the opportunity to provide more justification We thought long and hard before deciding on about this amendment, particularly debating this with the independent Tral Steering Committee, who agreed with this, along with Action for M.E., the patient charity, which collaborates with us in the trial. We have revisited these discussions in the light of the sub-committees concerns. We agree that it is unusual to ask for a two stage consent in a trial. At the same time, we do think there are significant arguments for doing this, which We are pleased to put forward tor the sub-committee to consider. a) Ethical reasons The two stage consent process, separated by a wesk, gives the potential participant a “cooling-of?” period to consider whether they really do want to make the major commitment to participating in the PACE trial, Controversy The largest patient charity in the UK (Action for M.E.) actively support the trial and are represented on the trial management group and provide an observer on the independent trial steering committee. In spite of this, two other patient charities (TYMES and the ME Association) have concems about the tral and one of them is even campaigning to stop the trial. Parliamentary questions have also been asked about the trial of the Medical Research Council and Department ot Health. Although we strongly believe these concems and reasoning are due to misunderstandings, we think it wise of us to allow a significant period of consideration by potential participants in the light of these concerns. incidentally, Action for M.E are fully supportive of the tral in spite of the concems of others. Commitment The cooling-off period also allows patients to carefully consider their commitment in travelling to the clinic cente for both treatment and research assessments, which can be particularly difficult for patients with major disabilities related to activity, such as travelling. Concentration problems affecting the decision to participate Because Chronic Fatigue Syndrome / myalgic encephalomyelitis (CFS/ME) can affect concentration and memory, we think allowing more than a usual time to decide whether to join the full tial is reasonable and justified. Dealing with ineligibility The two stage procedure also allows us to soften the blow of non-eligiility, since participants will not have their hopes of participation raised (as would be the case in a one-stage consent) only to have them dashed if they were not eligible. Since some patients will be ineligible due to having a psychiatric disorder, we believeMREC: 22Noverber 2004 305 SSROTWBA2850 this 1s important. They will also have the consolation of knowing that they have contributed to research into this mysterious illness by having contributed baseline data that will be analysed even though they will not be participants in the trial itself. With a one stage procedure, this data would be lost b) Practical reasons The eligibility screenmg involves a standardised psychiatric interview, which allows confirmation of the diagnostic cnteria, as well as making sure that participation in the trial is in the patient's interests. For instance if the patient also has significant post-traumatic stress disorder, it might be more appropriate for the patient to have this treated rather than entenng the trial. This interview will be audiorecorded in order for any borderline decisions or interpretations to be decided by a psychiatnst/centre leader. This requires time, which would be available within the two stage consent procedure ¢) Good clinical care We believe that this procedure would allow better clinical care of the patient. It allows the clinic doctor to plan further treatment that can then be offered to the ineligible patient as a postive outcome from the baseline data collection that the patient has participated in. 2. What happens to the audiorecordings after 20 years? The excerpt from your letter reads as follows. “There is no information in the Patient Information Sheet about what will happen to recordings of interviews after the 20 year period has elapsed.” We agree that this is not in the Patient Information Sheet. We nave added this statement “Only the research team will listen to these recordings, which will be kept sate in computerised form at the hospital for 20 years, After that time, all files of the recordings will be permanently deleted and all CDs of recordings destroyed.” 3. Possible coercion in offering additional treatment after the trial is over. The excep! from your letter reads as follows: “It was felt that the Patient Information Sheet is potentially coercive in that the paragraph entitled ‘Will my treatment stop suddenly at the ond of the trial’, [Page 90] it suggests that the three additional procedures may only be available to subjects who have participated.”UREC 22 Roveribar 2004 401s IsrcTNeszesoo8 This procedure was in the original protocol version 1 previously approved by the MREC, but only for those receiving Standardised Specialist Medical Care (SSMC), since they had not received a supplementary therapy within the trial Since then we have debated for a long time the question as to whether adcitional treatment should be offered to all participants whatever arm of the trial they were in We decided it would be more ethical to offer additional treatment to all participants who needed it after their participation in the trial, no matter what arm of the tial they had been in, since there would be some participants who did not improve in all arms of the trial. We also believed that this offer would better reflect the equipoise within the tral and the tralists. We would argue that it Is not coercive to state the fact that not all centres are able to offer these treatments outwith the trial. All the three additional therapies are available in four out of the six PACE trial centres. However, in two centres, not all treatments are available since services for CFS/ME are under-funded This is generally the case throughout the National health Service. We believe that patients would want to be informed of their real choices and altemative treatments. 4. Inclusion and exclusion criteria should be included in the Patient Information Sheet. The excerpt from your letter reads as follows. “4 was thought that there is a case for the inclusion/exclusion criteria, or some information about them being included in the Patient Information Sheet particularly in view of the use of the two stage consent procedure.” We are grateful for this sensible suggestion, with which we agree. We have amended the Patient Information Sheet to include these criteria. The pertinent part of the Patient Information Sheet now reads: “How do | qualify for your study? You must be diagnosed by us as having CFS/ME. Fatigue or lack of energy must be your main problem, and it must be sufficiently severe and cisabing. You must be at least 18 years old and be able to read and understand English. What could exclude me from your study? ‘You could have CFS/ME but still not qualify for our study. For instance, if + another condition, apart from CFS/ME, might also be causing your fatigue + you have tned one of the treatments in another fatigue clinic + you have another health problem that would not be helped in the trial + you would not be able to get to the hospital regulerly for your treatment. Other reasons may make it sensible to exclude you from our study. For instance,REC: 22 November 2006 S015 IsroTNSsz86008 pregnant women and women who are trying to get pregnant should not join our study. And we will be asking women who could get pregnant to use an effective contraceptive and to tell their GP and their clinic doctor they do get pregnant Our study would not harm a pregnant woman or her baby, but we would want to agjust their treatment and check whether they are taking any new medication IF you think there may be a reason why you should not join our study, it is very important that you tel us We will let you know if it is safe for you to join our study.” Documents reviewed We note in your letter (3° November 2004) that the remaining documents submitted to the MREC under amendment 2.1 (22 October 2004) have not yet been reviewed, and ask that you kindly consider these alongside this further amendment. With good wishes, Yours sincerely, hea Profe$sor Peter D White On behaff of professors Michael Sharpe and Trudie Chalder Principal Investigators Ene: Participant Information Sheet version 15, 22 November 2004 Substantial Amendment Form 2.2(COREC) NOTICE OF SUBSTANTIAL AMENDMENT For use in the case of all esearch other than clinical trials of investigational medicinal products (CTIMPs) For substantial amendments to CTIMPs, applicants should use the EU-approved netice of ‘amendment form available at www.corec.org.uk/amendments.htm This form cannot be accepted for CTIMPs. To be completed in typoscript by tho Chiof Investigator and submitted to the Research Ethics Committee that gave a favourable opmion of the research ("the main REC’). In the case of multi-site studies, do not send copies to other RECs unless specifically notified to 00 so by ihe main REC. Details of Chief Investigator: Name: Address" Telephone: E-mail. Fax: Professor Peter D White clo Julia DeCesare PACE Trial Manager Barts and the London Queen Mary's School of Medicine and Dentistry Department of Psychiatry Institute of Community Health Sciences Room 3.112 3rd Floor, Dominion House St Bartholomew's Hospital London EC1A 7BE Direct fine: 620 7601 8108 PACE trial centre number. 029 7601 8160 p.d.white@omul ac.uk 020 7600 5201 Fulltitle of study: ‘Short file of tral: Pacing, graded Activity, and Cognitive behaviour therapy; a randomised Evaluation Long title of trial A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome / myalgic encephalomyelitis or encephalopathy Research sponsor: Queen Mary, University of London, with other local sponsorship arrangements at each centre. Notice of amendment (non-CTIMP), Version 4 0, May 2004Name of main REC: West Midlands MREC Nain REC reference number: MREC/O2I7189 Date study commenced: | The trial aims to open to randomisation on the 4" | January 2005, Protocol reference (if applicable), | ISRCTN number: ISRCTN54285004 current version and date: MIRC code number: 0200434 Final protocol Protocol version number 2.0 Protocol date: 18.11.2004 A further full protocol, protocol version 3.0, incorporating the following amendments will be submitted in due course. Amendment number and date: Protocol Amendment 2.2, 24 November 2004 ‘Type of amendment (indicate all that apply) (a) Amendment to information previously given on the REC application form Yes No oO Ifyes, please referto relevant sections of the REC application in the "summary of changes” below (&) Amendment to the protocol Yes [J No o Ifyes, please submit either the revised protocol with a new version number and date, highlighting changes in bold, or a document listing the changes and giving both the previous and revised text (c) Amendment to the information sheet(s) end consent form(s) for participants, or to any other supporting documentation for the study Yes [& No o Ityes, please submit all revised documents with new version numbers end dates, highlighting new text in bold Notice of amendment (now-CTIMP), Version 1.0, May 2004‘Summary of changes Briefly summarise the main changes proposed in this amendment Explain the purpose of the changes and their significance for the study. Supporting scientific information should be given (or enclosed separetely) where the amendment significantly alters the research design or methodology, or could otherwise affect the scientific value of the study. We are grateful for the opinion of the Research Ethics Committee sub-committee, from the meeting held on the 25" October 2004, regarding amendment 2.1, dated 22 October 2004. We are pleased to responc to these suggestions below. 7. The two stage consent procedure The excerpt from your letier reads as follows: “The members were unable to understand the need for a two stage consent procedure. It is typical of many studies that the subject's consent to the study is obtained prior to eligibility screening - which might the fine them to be ineligible. This is appropriate since it ensures that no trial-related procedures are performed without consent. They did not feel that you had adequately justified a more complex procedure and consent and do not believe that the second stage consent form adds anything to the consent obtained at the first stage.” We both acknowledge and apologise for the fact that we did not adequately explain our rea: behind the two stage consent procedure, and we are pleased to have the opportunity to pro more justification. We thought long and hard before deciding on about this amendment, particularly debating this with the independent Triel Steering Committee, who agreed with this, along with Action for M.E., the patient charity, which collaborates with us in the trial. We have revisited these discussions in the light of the sub-committees concems. We agree that it is unusual to ask for a two stage consent in a trial At the same time, we do think there are significant arguments for doing this, which we are pleased to put forward for the sub-committee to consider. a) Ethical reasons The two stage consent process, separated by 2 week, gives the potential participant a “cooling-off" period to consider whether they really do want to make the major commitment to participating in the PACE trial Controversy ‘The largest patient charity in the UK (Action for M.E.) actively support the trial and are represented on the trial management group and provide en observer on the independent trial steering committee. In spite of this, two other patient charities (TYMES and the ME Association) have concems about the trial and one of them is even campaigning to stop the trial Parliamentary questions have also been asked about the trial of the Medical Research Council and Department of Health. Although we strongly believe these concems and Feasoning are due to misunderstandings, we think it wise of us to allow a significant period of consideration by potential participants in the light of these concems. incidentally, Action for M.E. are fully supportive of the trial in spite of the concems of others, Notice of amendment [nor-CTIMP), Version 1.0, Mey 2004Commitment ‘The cooling-off period also allows patients to carefully consider their commitment in travelling to the clinic centre for both treatment and research assessments, which can be particularly difficult for patients with major disabilities related to activity, such as travelling, Concentration problems affecting the decision to participate Because Chronic Fatigue Syndrome / myalgic encephalomyeltis (CFS/ME) can affect concentration and memory, we think allowing more than a usual time to decide whether to Join the full tral is reasonable and justified. Dealing with ineligibility The two stage procedure also allows us to soften the blow of non-eiigibilty, since participants will not have their hopes of participation raised (as would be the case ina one- stage consent) only to have them dashed if they were not eligible. Since some patients will be ineligible due to having @ psychiatric disorder, we believe this is important They will also have the consolation of knowing that they have contributed to research into this mysterious illness by having contributed baseline data that will be analysed even though they will not. bbe participants in the trial itself. With a one stage procedure, this data would be lost. b) Practical reasons The eligibility screening involves a standardised psychietnc interview. which allows confirmation of the diagnostic criteria, as well as making sure that participation in the tral is in the patient's interests. For instance if the patient also has significant post-traumatic, stress disorder, it might be more appropriate for the patient to have this treated rather than entering the trial. This interview will be eudiorecorded in order for any borderline decisions or interpretations to be decided by a psychiatrist/centre leader. This requires time, which ‘would be available within the two stage consent procedure ©) Good clinical care We believe that this procedure would allow better clinical care of the patient. It allows the diinic doctor to plan further treatment that can then be offered to the ineligible patient es a positive outcome from the baseline data collection that the patient has participated in, 2. What happens to the audiorecordings after 20 years? The excerpt from your letter reads as follows: “There is no information in the Pationt Information Sheet about what will happen to recordings of interviews after the 20 year period has elapsed.” We agree that this 1s not in the Patient Information Sheet, We have added this statement “Only the research team will listen to these recordings, which will be kept safe in ‘computerised form at the hospitel for 20 years. After that time, all fles of the recordings will be permanently deleted and all CDs of recordings destroyed.” 3. Possible coercion in offering additional treatment after the trial is over. The excerpt from your letter reads as follows. “it was felt that the Patient Information Shoot is potentially coercive in that the paragraph entitled ‘Will my treatment stop suddenly at the end of the trial, [Page $0] it suggests that the three additional procedures may only be available to subjects Notice of amendment (non-CTIMP), Version 1 0, May 2004who have participated.” This procedure was in the original protocol version 1 previously approved by the MREC, but only for those receiving Standardised Specialist Medical Care (SSMC), since they had not received a supplementary therapy within the trial. Since then we have debated for a long time the question as to whether additional treatment should be offered to all participants whatever arm of the trial they were in. We decided it would be more ethical to offer additional treatment to all participants who needed it after their participation in the tial, no matter what arm of the trial they had been in, since there would be some participants who did not improve in all arms of the trial. We also believed that this offer would better reflect the equipoise within the trial and the trialists. ‘We would argue that it is not coercive to state the fact that not all centres are able to offer these treatments outwith the trial. All the three additional therapies are available in four out of the six PACE trial centres. However, in two centres, not all treatments are available since services for CFS/ME are underfunded. This is generally the case throughout the National heelth Service. We believe that patients would want to be informed of their real choices and alternative treatments. 4, Inclusion and exclusion criteria should be included in the Patient Information Sheet. The excerpt from your letter reads as follows: “It was thought that there is a case for the inclusion/exclusion criteria, or some information about them being included in the Patient Information Sheet particularly in view of the use of the two stage consent procedure.” We are grateful for this sensible suggestion, with which we agree. We have amended the Patient Information Sheet to inckide these ciitena. The pertinent part of the Patient Information Sheet now reads “How do | qualify for your study? You must be diagnosed by us as having CFS/ME Fatigue or lack of energy must be your main problem, and it must be sufficiently severe and disabling. You must be at least 18 years old and be able to read and understand English. What could exclude me from your study? You could have CFS/ME but still not qualify for our study. For instance, i + another condition, apart from CFSIME, might also be causing your fatigue + you have tried one of the treatments in another fatigue clinic + you have another health problem that would not be helped in the trial + you would not be able to get to the hospital regularly for your treatment. Other reasons may make it sensible to exclude you from our study. For instance, pregnant ‘women and women who are trying to get pregnant should not join our study. And we will be asking women who could get pregnant to use an effective contraceptive and to tell their GP and ther clinic doctor if they do get pregnant. Our study would not harm a pregnant woman orher baby, but we would want to adjust their treatment and check whether they are taking any new medication. Notice of amendment (non-CTIMP), Version 1.0, May 2004If you think there may be @ reason why you should not join our study, it is very imporant that you tell us. We will let you know f it is safe for you to join our study” ‘Any other relevant information Applicants may indicate any specific ethical issues releting to the amendment, on which the opinion of the REC is sought. List of enclosed documents Indicate revised version numbers and dates and highlight all changes in bold or underline. Participant Information Sheet version 15, 22 November 2004 Please see above toxt for details of paragraphs changed. Declaration + I confirm that the information in this form is accurate to the best of my knowledge and | take full responsibility for it. + I consider that it would be reasonable for the proposed amendment to be implemented. Signature of Chef Investigator. Print name. Rete Dae See Date of submission: 24TS Doves Lose Notice of amendment (non-CTIMP), Version 1.0, May 2004SL2? Vale notice cf substental amerciment Version 2, October 2004 West Midlands Multi-centre Research Ethics Committee Professor Pater D White 27 Highfield Road fo Julia DeCesare EdaDeO) PACE Thal Manager Binion Barts and the London ‘Queen Mary's Schoo! of Mediane and Dentistry Tel, 0121 205 2549 Depariment of Psychiatry Fax: 0121 245 2519, Ingtitute of Community Health Sciences Room 3.112 2° Floor, Dominion House St Bartholomews HospitelLondon EC1A 7BE Dear Professor White , Study title A randomised, controlled trial of adding cognitive behaviour therapy, graded exercise therapy, or adaptive pacing therapy to usual medical care, compared to usual medical care alone for the chronic fatigue syndrome [ME] PACE trial REC reference: MREIO2/7/89 Amendment number: 2.2 Amendment date: 24 November 2004 Thank you for submitting the above amendment, which was received on 25 November 2004 | can confirm that this 1s a valid notice of ¢ substantial amendment and will be reviewed by the Sub-Committee at its next meeting. Documents received The documents to be reviewed are as follows Notice of Substantial Amendment Participant Information Sheet, Version 15, 22 November 2004 Notification of the Gommittee’s decision The Committee wil issue an ethical opinion on the amendment within a maximum of 36 days from the date of receipt Management approval Al investigators and research collaborators in the NHS should notify the R&D Depariment for tho relevant NHS care organisation of this amendment and check whether it affects local management approval of the research. The Ceniral Offce for Research Ethics Committees is responsibwe for the (Gperatlonat qienepernere of MunTicerere Research Fufers CommrttectSL27 Valid tice of sutstantal amendment Yertslon 2, Ocober 2004 4 Please quote this number on all correspondence _ [TREC reference number}: Yours sincerely, Nicola Murphy ) Assistant Administratie West Midlands Multi-centre Research Ethics Committee 45 December 2004 27 Hightield Road Professor Peter D White Edgbaston clo Julia DeCesare i Bimal PACE Trial Manager BIR ADE Barts and the London Tel: 0121 245 2544 Queen Mary's School of Medicine and Dentistry Fax: 0121 245 2519 Depariment of Psychiatry Institute of Community Health Sciences Room 3. 112, 3° Floor, Dominion House St Bartholomew's Hospital London EC1A 7BE Dear Professor White , Study title: A randomised, controlled trial of adding cognitive behaviour therapy, graded exercise therapy, or adaptive pacing therapy to usual medical care, compared to usual medical care alone for the chronic fatigue syndrome [ME] PACE trial REC reference: MRE/O2/7/89 Amendment number: 2.2 Amendment date: 24 November 2004 ‘The above amendment was reviewed by the Research Ethics Committee Sub Committee at the meeting held on 14 December 2004. Ethical opinion ‘The members of the Committee present decided that it could not give a favourable ethical opinion of the amendment, for the following reasons: 1. Whilst the investigators state that treatment will be available fo participants on completion of the study, but that not all troatmonts will be available at all centres, this position is no! accurately reftected in the paragraph of the Patient Information Sheet entitled ‘Will my treatment suddenly stop ....’ This paragraph includes the sentence ‘This extra [continuing] treatment is for patients who join our study; 1 may not be available outside our study’. The members of the Sub Committee believe ihat, firstly, this is not an accurate reilection of the true position for participants and, secondly, it can be interpreted as boing coercive in suggesting that the only way to get certain treatments is in consequence of having joined the study. 2, Please therefore consider revising this paragraph. regret to inform you that the amendmentis therefore not approved. ‘The study should continue in accordance with the documentetion previously approved by the Committee. Modifying the amendment IF you think that it would be possible for you to modify or adapt the amendment in such a way as to address the Committee's concerns, it is open to you to submit a revised notice of amendment SOPs version 7.0 datec Feuruary 2004 SL30 —Unfavouradle opinion of amendment The Central Office for Research Ethics Committees is responsible for the ‘peratianal management of Multicentre Research Ethics Committeeson the standard form, The form should indicate that this is a modification of the above amendment Documents reviewed “The documents reviewed at the meeting were: + Notice of Substantial Amendment + Participant Information Sheet, Version 1, 22 November 2004 Membership of the Committee The members of the Ethics Committee who were present al the meeting are listed on the attached sheet, This Committee is recognised by the United Kingdom Ethics Committee Authority under the Medicines for Human Use (Clinical Trials) Regulations 2004, and is authorised to carry out the ethical review of clinical trials of medicinal products, ‘The Committee is fully compliant with the Regulations as they relate to ethics commitiees and the conditions and principles of good clinical practice The Committee is constituted in accordance with the Govemance Arrangements for Research Ethics Committees (July 2001) and complies fully with the Standard Operating Procedures for Research Ethics Committees in the UK. [REC reference number: MRECIO27/69.__ Please quote this number on all correspondence Yours sincerely, Anne McCullough [Mrs] Committee Administrator Enclosures _ List of names and professions of members who were present at the meeting SOPs version 1.0 dated February 2004 SL30_—_Unfavourable opinion af amendmentComposition of MREC West Midlands Members: 14 December 2004 Attendance _| Name Profession Dr Jammi Rao Chairman - | Director of Public Health | Dr Steve Bain Reader in Diabetic Medicine VS Mr Nige! Ballantine Vice Chairman Specialist Clinical Pharmacist vs Dr Harshad Desai Consultant Physician Ms Debra Easlea Oncology Research Sister Cinical Research Associate Mr Timothy James Senior Lecturer in Law Dr R Jubb Consultant Rheumatologist Rev Dottie Johnson Lay Member Miss Nancy Leslie Lay Member Prof Alexander MeNeish__| Retired Consultant Paediatrician vs Mrs Pat Moseley Lay Member Ms Christiane Neumann —_| Clinical Nurse Specialist Dr A Roddam Senior Statistician KEY: Member attended WS Member submitted written comments Member of Sub Committee