9 January 2013

Present

Professor Julietta Patnick (Chair)

Professor Dame Valerie Beral

Dr Lucy Carpenter Kath Moser

Professor Sir Richard Peto

Professor Amanda Ramirez

Professor Malcolm Reed

Professor Sir Mike Richards Sarah Sellars

Margot Wheaton Richard Winder

In attendance

Professor Janet Darbyshire Jenny Rusby

Hayley Abbiss (notes)

Apologies

Dr Robin Wilson

Documents circulated in advance:

• Agenda
• Draft revised trial protocol (Dec 2012)
• Draft patient information leaflet (Dec 2012)
• Minutes of TMG meeting 11 January 2012

Documents circulated at meeting:

• Trial progress at end of 2012; graphs of trial cumulative numbers by date
• Article: Extending the age range for breast screening in England: pilot study to assess the feasibility and acceptability of randomization (JMedScr)
• Article: The benefits and harms of breast cancer screening: an independent review (The Lancet)

1. Welcome and introductions (Julietta Patnick (JP))

Janet Darbyshire (JD) and Jenny Rusby from the trial Data Monitoring and Ethics Committee (DMEC) were welcomed to observe the meeting.

It has been one year since the last TMG meeting (by telephone conference). Progress on revising the protocol and information leaflet was delayed while we awaited the outcome of the Marmot Review. The Review (reporting at the end of Oct 2012) supported the continuation of the screening programme and, importantly for this trial, said “The impact of breast screening outside the ages 50-69 years is very uncertain. The Panel supports the principle of the ongoing trial in the UK for randomising women under age 50 and above age 70 to be invited for breast screening.”

2. Minutes of the last meeting (11 January 2012) and matters arising 

The minutes were accepted as an accurate record of the meeting.

Matters arising:

Sarah Sellars (SS) gave an update on digital mammography: out of the 80 breast screening units, 66 were now fully digital and 4 had no digital machines (due to drop to 3 by the end of Jan 2013).

Kath Moser (KM) confirmed that the complaint received from a patient randomised in aged 72 had been referred to Janet Darbyshire (JD), Chair of the DMEC.

JP reported that the National Research Ethics Service recently received a Freedom of Information Request about the trial; they are going to supply the information requested with names redacted.

3. Trial update

a) revised protocol and patient information leaflet

Following the outcome of the Marmot Review the protocol and the trial patient information leaflet have been revised.

The group discussed the protocol and some further minor revisions were suggested. It is not intended to revise the protocol again and therefore it needs to be phrased in such a way to avoid necessitating further revision. KM confirmed that all members of the TMG will be co-authors of the protocol, and linked publication, as agreed at the TMG Jan 2012. JD requested that her DMEC membership details be amended to remove ‘statistician’ and replace with ‘epidemiologist’.

Action: KM to amend JD’s details.

Any further comments to be sent to KM by 18 January. KM to action the changes already agreed and any further suggested changes.

Action: All to send any further comments regarding the protocol to KM by 18 January 2013.

Finalising the protocol will be delegated to the co-investigators. Once finalised, the revised protocol will be submitted to the ethics committee as part of a notice of substantial amendment.

Action: KM to make further revisions to protocol and patient information leaflet and send to Ethics for approval, by end February 2013.

It was agreed that the final protocol should be submitted to a journal for peer- reviewed publication. Lancet Oncology was suggested.

Action: KM to submit protocol to journal for publication.

JD suggested that the co-investigators develop a statistical analysis plan although the full plan could be finalised at a later date before conducting the final analysis.

Action: Co-investigators to consider developing a statistical analysis plan.

The TMG agreed the appointment of Dr Gillian Reeves (GR) as the independent statistician on the DMEC. It was noted that GR, being located within the Cancer Epidemiology Unit, will have access to data that will not be available to the TMG, and as such the proprieties of the role must be observed in order not to compromise the integrity of the trial.

The revised patient information leaflet, which will form part of the published protocol, was discussed. Many comments were made and amendments suggested. It was agreed that some further extensive revisions were required following which it would be circulated again.

Action: KM to further revise the patient information leaflet and circulate by 18 January 2013 for approval.

The possibility that a woman may wish to attend for screening but opt out of the trial was discussed. However the TMG agreed it was not necessary to mention this within the leaflet as, should a woman object to being in the trial, then she could be removed from the trial analysis at that time.

b)   progress to date

KM described trial progress as outlined in the 2 circulated handouts. An estimated 800,000 women have now been randomised. As there was not time to describe other aspects of progress it was agreed that KM would circulate the committee with this information.

Action: KM to email the TMG with an update on progress.

4. Any other business

Proposal to extend the trial at older ages

Richard Peto (RP) highlighted the benefits of extending the trial by inviting the older women who had been randomised in aged 71-73 to a further two extra screens (at ages 74-76 and 77-79 years). Life expectancy in women is increasing and women in their mid 70’s are generally still in good health. Stopping sending invitations could send the message that there is a lowering of risk, which is erroneous. Offering this additional screening will add to the power of the trial.

The 5 pilot sites started randomising women in June 2009. As this is over 3 years ago, there would be older women who had been randomised in aged 71-73 and who would now be eligible, once the approvals are in place, to be invited in the next screening round. By June 2013, five other centres will be in this position. VB said it was important to start offering additional screening to the older women as soon as possible so as not to miss too many women. JP commented that the units need time to prepare for the changes, but if ethical approval was obtained in March they should be able to start in autumn 2013.

The trial, as currently formulated, is mandatory. Discussions should be had regarding the compulsory/voluntary nature of offering additional screening beyond the age of 73. If this is not mandatory, some screening units will opt out due to workload issues and this could result in the participating units being unrepresentative of the whole.

Margot Wheaton (MW) commented that offering additional screening will require changes to the NBSS software.

Action: MW to start discussing computing implications and software developments required.

The costs of offering additional screening were discussed. Overall around 0.5M women could be offered additional screening after age 73. Costs incurred will include this additional screening, although uptake is not expected to be high, and also the computing development. It was agreed that Public Health England (PHE) should be approached now and with a view to seeking approval for 18 months funding (until March 2015), estimated at £1.5-2M, on the recommendation of the TMG. Mike Richards (MR) suggested that the group could use 2014/15 to make a case for requesting further funding in the following years, looking at the long run and potential for reduced costs. He suggested that once recruitment stops then the money saved could be used to continue screening the existing older women within the study as they age; the advantage being that a cohort getting older will give a more reliable answer.

Action: Submit funding request for additional 18 months to PHE.

VB suggested the possibility of going to a research funding body if PHE won’t provide funding.

MR suggested that the different options are costed at this stage so that it is clear what the funding profile will be. This was agreed.

Action: KM to prepare costings.

5. Date of next meeting

January 2014, date to be confirmed.

Action: KM/HA to email TMG with proposed date.