CFS/ME PACE Trial -Parliamentary Questions

[Guest guest]

From: Ralph

On 7th May 2012 Professor Malcolm Hooper provided The

Countess of Mar with a list of questions about the PACE

Trial (*Questions submitted by Professor Malcolm Hooper

to The Countess of Mar re: the PACE Trial for the attention

of the Minister of State for Universities and Science, the Rt

Hon Willetts MP, who is responsible for the Medical

Research Council*).

The Countess of Mar kindly agreed to re-word and table the

questions to which Her Majesty’s Government are obliged

to provide answers (*PACE Questions as tabled*), these

having being refined by her to 6 key questions.

One question was altered by the Clerk and it is notable that

the second question:

*To ask Her Majesty’s Government which disease or

condition was being studied in the PACE Trial*

was not put in by the Clerk, but the Countess of Mar

assures us that it should go in today.

Please check progress on the Parliamentary website.

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http://www.meactionuk.org.uk/Questions-re-PACE-Trial.htm

Questions submitted by Professor Malcolm Hooper to The

Countess of Mar re: the PACE Trial for the attention of the

Minister of State for Universities and Science, the Rt Hon

Willetts MP, who is responsible for the Medical

Research Council

7th May 2012

Clinical trial registration has become a pre-requisite for

publication in reputable medical journals, leaving

non-compliant trial *findings* with uncertain status.

Given that lack of transparency in clinical trial conduct,

publication bias, non-adherence to the published Protocol,

selective reporting bias and the omission of important data

from published trials that can lead to erroneous

recommendations for treatment are serious problems in

medical research, and that clinical trials registration is

essential to avoid these problems:

1. Will the Minister confirm that failure to comply with

proper clinical trial registration undermines public

confidence in medical research, and that it is not

acceptable for a publicly-funded trial to be improperly

registered

2. Will the Minister therefore ascertain and explain why

the PACE Trial is incompletely registered in the ISRCTN

(International Standardised Random Controlled Trial

Number) Register (the PACE Trial registration being

ISRCTN54285094), given that accurate registration,

including the recording of all changes in procedure from the

point of registration onwards, is required as a condition for

publication in reputable journals

3. Will the Minister ascertain from the Editor-in-Chief of

The Lancet and explain why an article reporting selective

outcomes of the PACE Trial was deemed acceptable for

publication in The Lancet (The Lancet: 2011, 5th March:

377:823-836), when the Editor-in-Chief, Dr Horton,

is a member of the International Committee of Medical

Journal Editors (ICMJE) which *requires, as a condition of

consideration for publication, registration in a public trials

registry* and that such registration must be completed in

all 20 fields in the WHO minimal data set and will be

considered inadequate if it has missing fields or fields that

contain uninformative terminology, as is the case with the

PACE Trial, where changes from the approved Protocol

have not been recorded in the Register as required:

previously logged information has been removed from the

trial record; fields are missing entirely and fields contain

uninformative terminology, even though Current Controlled

Trials (CCT), a body which includes representatives from

both the MRC and the DoH, states: *CCT does not remove

information from a record, or overwrite previous information,

but will instead add any updated information, along with a

date stamp to show when changes were made to the trial

record*

4. Will the Minister confirm which disease or condition

was being studied in the £5 million PACE Trial that was

co-funded by the MRC, the DoH, the DWP and the

ish Chief Scientist’s Office and which purported to be

studying *CFS/ME* (CFS being a synonym for ME and

classified in the WHO ICD-10 at G93.3), yet the Chief

Principal Investigator (PI), Professor White, has

confirmed in writing that the PACE Trial did not purport to

be studying ME, even though the trial documentation refers

to *CFS/ME* and ethical approval and funding were granted

on the basis that the PIs would be studying *CFS/ME*

5. Will the Minister ascertain and explain why the

PACE Trial sponsor was changed from The MRC Clinical

Trials Unit to The Medical Research Council and then to

the Queen University of London (UK) and why these

changes are not recorded in the Register (for the record,

the sponsors of the PACE Trial are referred to in The

Lancet article as being the Medical Research Council, the

ish Chief Scientist’s Office, the Department of Health

in England and Wales and the Department for Work and

Pensions)

6. Further, given that the WHO International Clinical

Trials Registry Platform (whose Scientific Advisory Group

includes The Lancet’s Dr Horton) that is linked to

the major ISRCTN Register requires that those responsible

for completing the Register *Must not have conflicts of

interest over which trials or trial information to register* and

must *Collect full Trial Registration Data Set*), will the

Minister clarify if the change of sponsor was related to a

conflict of interest on the part of one of the UK Directors of

the ISRCTN responsible for the registration and tracking of

changes (Dr Watkins of the MRC Neurosciences and

Mental Health Board, on which two of the PACE Trial PIs,

Professors White and Trudie Chalder also served, as

Watkins authored the 2003 MRC *CFS/ME Research

Strategy* that recommended further research into the

psychosocial interventions graded exercise therapy [GET]

and cognitive behavioural therapy [CBT] as opposed to any

biomedical studies into ME/CFS and his support for the

PIs is a matter of record)

7. Will the Minister ascertain the real reason and clarify

why the scoring instruments were changed once the PACE

Trial was underway (ie. on entry, participants’ results were

scored using one measurement scale and on completion

were scored using another measurement scale) and why

this change is not recorded in the Register, since many

informed people find the PIs’ proffered explanation to be

unconvincing (*we changed the original bimodal scoring of

the Chalder fatigue questionnaire (range 0–11) to Likert

scoring to more sensitively test our hypotheses of

effectiveness*), given that in the FINE Trial (a sibling of the

PACE Trial wholly funded by the MRC), when scored

bimodally the interventions did not achieve statistical

significance, but when a post-publication post-hoc analysis

was carried out using Likert scoring, it was possible to

demonstrate a clinically unimportant but statistically

significant effect

8. Will the Minister ascertain and explain why the

recovery statistics and other outcomes that were defined in

the published Protocol (such as the number of PACE Trial

participants who have returned to gainful employment) have

not been published, given that such outcomes are of

considerable public interest and are of importance to the

funders (the PACE Trial being the only clinical trial that the

DWP has ever funded and it did so on the understanding

that the interventions would return participants to

employment)

9. Will the Minister ascertain from the Chief PI why he

lowered the definition of *normal* physical function: is the

Minister aware and content that in 2002, the Chief PI

calculated the *normal range* for physical function at the

outcome of the PACE Trial to be an SF-36 (physical

function) score of 75 or above out of 100, yet when he

performed the same calculation in 2011 for publication in

The Lancet, he had re-calculated this figure to be just 60

out of 100, which is five points lower than the score

required to enter the trial and is 15 points lower than his

written commitment given in 2006 to the West Midlands

Multi-Centre Ethics Committee (MREC) that the score

required for a *categorical positive outcome* would be 75,

thus *reasserting a ten point score gap between entry

criteria and positive outcome*, and why these changes are

not recorded in the Register

10. Will the Minister specifically request an explanation

from the Chief PI why both primary outcome figures (fatigue

and physical function) were changed so that they were

lower than those required for entry to the trial (ie. a

participant could actually deteriorate during the Trial yet

still fall within the PIs’ amended *normal range* at the

completion of the Trial), and how such a situation can be

regarded as good scientific practice

11. In the light of this, will the Minister call for an urgent

independent re-analysis of the raw data in order to know

the outcomes as listed in the published Protocol

12. Will the Minister confirm what steps he proposes to

take to rectify this apparent scientific fraud that is already

causing iatrogenic harm to patients with the neuroimmune

disorder ME, since the Chief PI is on record in his keynote

address at the BACME conference held on 14th-15th

March 2012 as stating that *pacing* (ie. living sensibly

within one’s physical limits) should be removed from the

clinicians’ lexicon, as referring to the PACE Trial as a

*magnificent achievement* and as urging the extensive use

of the interventions CBT and GET

13. Given the non-conformity with the ISRCTN Register

requirements, will the Minister clarify the MRC’s legal

position as a co-funder of the PACE Trial regarding the

subsequent reliance by NICE and the DWP on the

outcome as reported in The Lancet which has such

potentially harmful clinical implications for those with ME

due to the demonstrated immune and cardiovascular

dysfunction

14. Since no recovery statistics have been published, is

the Minister aware of the misrepresentation of the PACE

Trial outcome and false interpretation of the reported

outcome such as those by Bleijenberg & Knoop who

asserted that about 30% had *recovered* (Lancet 2011:

doi:10.1016/S0140-6736(11)60172-4) and by Collin and

Crawley et al who compounded this error by stating:

*Evidence from a recent evidence (sic) trial of cognitive

behavioural therapy and graded exercise therapy indicated

a recovery rate of 30-40% one year after treatment* (BMC

Health Services Research 2011:11:217)

15. Does the Minister agree that without full trial

information in the Clinical Trials Register, readers cannot

fairly assess the validity of the reported PACE Trial findings

because changes which might alert Register users to

possible problems within the conduct of the PACE Trial

have not been recorded or are recorded in a way that is

misleading, thereby undermining the rationale of trial

registration.

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http://www.meactionuk.org.uk/PACE-Questions-as-tabled.htm

Countess of Mar

Questions for Written Answer

• To ask Her Majesty’s Government to confirm that it

isnecessary for a publicly funded trial to be

properlyregistered in the ISRCTN (International

Randomised Controlled Trial Number) Register; that this is

a condition for publication in reputable journals and, if so,

whether they are satisfied that the PACE (Pacing, graded

Activity and Cognitive behaviour therapy: a standardised

Evaluation) Trial registration ISRCTN54285094 is complete

and includes records of all changes in procedure from the

point of registration onwards.

• To ask Her Majesty’s Government which disease or

condition was being studied in the PACE Trial that was

co-funded by the Medical Research Council, the

Department of Health for England and Wales, the

Department for Work and Pensions and the ish Chief

Scientist’s Office in light of the statement made by the

Chief Principal Investigator, Professor White, that the

PACE Trial did not purport to be studying ME (a synonym

for CFS/ME), when all the trial documentation, ethical

approval and funding refer to CFS/ME.

• To ask Her Majesty’s Government when and why the

PACE Trial sponsor was changed from the MRC Clinical

Trials Unit to The Medical Research Council and then to

the Queen University of London (UK) and why these

changes are not recorded in the ISRCTN Register and the

sponsors are described in the Lancet: 2011, 5th March:

377:823-836 as the Medical Research Council, the

ish Chief Scientist’s Office, the Department of Health

for England and Wales and the Department for Work and

Pensions.

• To ask Her Majesty’s Government why the recovery

statistics and other outcomes as defined in the published

Protocol of the PACE Trial have not been published in view

of their importance to the funders and the public interest.

• To ask Her Majesty’s Government why the *normal range*

for both PACE Trial primary outcome measures (fatigue

and physical function) were re-defined so that it was

possible for a participant to deteriorate on both measures

during the course of the Trial yet still fall within the Chief

Principal Investigator’s *normal range* .

• To ask Her Majesty’s Government, in the light of the

non-conformity of the PACE Trial with ISRCTN Register

requirements, what is the legal position of the Medical

Research Council as co-funder regarding the subsequent

reliance by the National Institute for Health and Clinical

Excellence and the Department for Work and Pensions on

the outcome as reported in the Lancet.

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