Information for prospective patients in the clinical trial of extending the age range for breast cancer screening has been updated at www.cancerresearchuk.org. After long term pressure from HealthWatch and others, it is good to see that the trial is now being described more openly. It is clearly stated that the policy on screening the extended age ranges will depend on the outcome of this trial, although that won't be known until 2022.
We were dissatisfied that the Research Ethics Committee (REC) did not appear to take our previous concerns seriously, so we sent an appeal letter on 29th December 2014. This letter is here. We itemised 20 issues that needed to be addressed by the REC. After regular prompting, we eventually received a reply dated 20th March 2015, Oversight of REC decisions is provided by the National Research Ethics Advisors’ Panel (NREAP). In summary, this body dismissed most of our concerns, and allowed the study to proceed unconditionally.
A flavour of its approach may be gained from the response to our very first concern number 1(a), which was about addressing the initial ethical approval given to this trial which has rolled over despite the rationale changing:
The committee do not seem to have addressed, as separate matters, the continuing REC approval of the original study followed by the question of a substantial amendment.
…and the response:
The Committee has stated that no data (published work, comments by breast cancer specialists) had been provided by you to back up the points made and it was felt that the criticisms of the study had no substance.
This was a question about what the REC had failed to do. Hence there was no need for any supporting data. The response makes no sense.
The REC's record keeping was shown to be inadequate, as the Panel “was unable to find any reference to third party written comments being considered in the REC minutes” regarding our question 1(b). The Panel thought that as the REC had told us in various emails that the issue had been addressed, then they had done so. Papering over the cracks?
The response to question 1(d) is odd. They seemed to think we were asking for information on how REC members voted. We were not. It is a mandatory requirement of Good Clinical Practice that REC members present at a relevant meeting must be documented in the Trial Master File. The reason we asked is to ensure that proper expertise was being used, especially statistical. There was no statistician on the REC which gave the original favourable opinion. We still don't know whether there was a competent statistician involved in the latest decision.
To our question 5, the Panel agreed that “the time lag between the submission of the original amendment and the submission of the final approved amendment was too lengthy”, and action has been taken to address this. Good news.
To our question 7, “The panel further noted that the length of a protocol is not related to its quality.” All of the clinical research experts who were shown the original protocol by ourselves were staggered that it was only eight pages. While quality of course bears no statistical relationship to length, there is rather a large difference between normal protocols which run to hundreds of pages including essential appendices, and one of only eight pages in length.
To our question 8, the subtext seems to be that there is doubt as to whether the matter of proper informed consent was fully discussed by the REC. It's rather strange to see the phrase “on the balance of probability” applied to whether this was the case. More papering over of cracks?
To our question 9, at least some of the disagreement stems from the REC's insistence on calling this an epidemiological study. It is not, it is a randomised controlled trial.
Is it really reasonable to assume that patients will separate in their minds information given to them about the current screening programme, and that given about the age extension trial – on the same occasion? The REC considers that it is (our question 10). We think women will be further confused.
If it's not the REC's job to ensure proper trial oversight, whose is it? (our question 11). The same applies to the DMEC issue.
Our question 14; the Panel says:
With regards to the Invitation Letter, the Chair acknowledges that the Committee should have seen this alongside all the other information. However, it is a standard letter that is sent to all women regardless of the study, and is outside of the REC remit to review.
So if the REC should have seen the letter, how is it outside their remit? The standard invitation letters can be very persuasive and contradict the tone of the research trial leaflet. Indeed, the letters are inviting women to an RCT, so they should NOT be the standard invitation.
It now appears that Professor Patnick is only a figurehead, as other more eminent people are responsible for the science (our question 15). Weasel words seem to prevail for much of the rest of the letter. For example:
16. The CI’s refusal to allow publication of the protocol
“The Committee was unable to comment, but the HRA supports publication of protocols as part of its transparency agenda. Under the HRA’s Freedom of Information Guidance, however it is recognised that Section 41 – Information provided in confidence, could be considered in certain cases as the protocol could reasonably have been submitted with the view that it is information provided in confidence.
So that's alright then. And:
17. No timescales.
“It is the responsibility of the Sponsor to ensure compliance and there is an expectation that researchers will do this.
This is asking why the REC failed to pin the investigators down regarding when they would comply with requirements. How is this in any way an answer?
In question 19 we asked why “There is no retrospective information to be given to women already enrolled in the light of these changes”, meaning changes in the science of screening. Here the Panel and the REC fail to differentiate between the standard age range, ie women aged 50-69 not in the trial, and the extended ranges of women invited to the trial (47-50 and 70-73). They both think that the same information applies to both groups. It doesn't, because risks and benefits are likely to be different.
The matter of GCP compliance is largely swept aside by the response to question 20. Two points stand out:
Apparently the investigators have been in equipoise all the time. Not if you look at the original trial summary, which says: “The age extension will proceed regardless of whether this study goes ahead or not, and therefore regardless of whether the phasing-in is randomised or not.”
GCP compliance is not the concern of the REC. Whose is it? For a trial of a drug or a device, it would be the MHRA. Who inspects publicly funded trials? Will there be an audit?
The Panel has made it clear that this is the end of the road, hence we have not replied, and have been mulling over the implications. HealthWatch is eager to learn what you think.