1. BIG BROTHER or friend in need?
Andrew Nunn
MRC Clinical Trials Unit at UCL
May 9th 2017

2. BIG BROTHER or friend in need
critical friend?

3. How do you view your trial’s DMC?
How does the DMC of which you are a member see its role?

4. The role of the DMC
DMC charters vary in their description of roles and responsibilities but these can usually be summarised by broad statements such as:
“To protect and serve trial patients and to assist and advise the Principal Investigators so as to protect the validity and credibility of the trial.”
“To safeguard the interests of trial participants, assess the safety and efficacy of the interventions during the trial and monitor the overall conduct of the clinical trial”
Damocles Study Group, Lancet, 2005

5. If independent oversight of trial conduct is important - how can it best be achieved?
In some settings the DMC represents the only available independent oversight.
In other instances the DMC complements the oversight provided a group such as the Trial Steering Committee

6. UK MRC Trial oversight model
“All [trials] should include an element of expert advice that is entirely independent of the Principal Investigators and the Host Institution involved. This will normally take the form of a Trial Steering Committee (TSC) and a Independent Data Monitoring Committee.”
“The role of the TSC is to provide overall supervision for the trial [and] advice through its independent chairman …. Involvement of independent members provides protection for both trial participants and PIs”

7. An added TOR?
The sponsors of the trial may ask a DMC to “review policy or to act as a scientific advisory board”
Wittes, Statistics in Medicine, 1993
More often a DMC may just choose to take on that role

8. What should a DMC do when a trial is going badly?
Ignore it? X
Comment in their recommendations? √
Make constructive suggestions for improvements? √
Work with the trial team to resolve the problems?

9. Impact of new treatment guidelines
New treatment guidelines recommendations emerging during the course of a study can present major challenges to the study team
Is the trial still addressing a valid question?
Is it ethical to continue to enrol patients to a treatment which is no longer recommended?
Should the trial be modified and if so how?

10. TB-HAART trial
Designed to determine the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per μl or more
BUT before enrolment was complete WHO made new recommendations

11. WHO 2009 Guidelines: ART for patients co-infected with TB and HIV
“Regardless of their CD4-cell counts, patients co-infected with HIV and tuberculosis (TB) should be started on ART as soon as possible after starting TB treatment.”

12. TB HAART trial: DMC response
“We understand the reasons behind the WHO recommendation to start ART in any HIV-infected patient with HIV, but we would respectfully suggest that this recommendation be accompanied by a caveat indicating that data are very limited in patients with CD4 cell counts >200/mm3 and more research is needed to determine the actual benefit in patients with less severe HIV disease.”
Statement following 3rd meeting of TB HAART DMC, April 2010

13. TB HAART trial 4th meeting of DMC
It was noted that “there was a caveat included in the WHO recommendations stating that for patients with higher CD4 counts the evidence for the benefits of treatment was weak and that further research was needed”.
“This statement provides ethical justification for the continuation of the TB-HAART study”.
Concern was expressed, however, that, even with the caveat, the recommendations would have “a chilling effect on research”.

14. Delayed stopping
At a meeting of the DMC for the CHAP trial of cotrimoxazole for children infected with HIV the significance of the effect size satisfied the Haybittle-Peto guideline for early stopping but there were insufficient data to say whether the beneficial effect was sustained beyond 6 months
The DMC, aware that this might have implications for WHO recommendations, consulted other experts and decided to delay recommending stopping for a further 8 months
When the results were released WHO proceeded to recommend that all children infected with HIV should receive cotrimoxazole

15. WHO recommendations pre-empting trial results
May 2016 WHO released new recommendations for the treatment of multi-drug resistant TB, based on “very low quality evidence” from cohort studies
These recommendations have had important implications for the STREAM trial which is currently assessing the newly recommended regimen
The STREAM DMC is providing valuable ongoing advice and support as to how the investigators should respond to this and other challenges

16. Initial pre-trial review
Initial review gives the DMC an opportunity to identify if they have any major concerns about the trial protocol which need to be addressed to before the DMC can take responsibility for trial oversight.
In practice the timing of this review is often too late in the process for major issues and concerns to be properly addressed.

17. A friend in need
In some circumstances the DMC may chose to go way beyond the call of duty, assisting the trial team with a trial with issues such as
problems with enrolment and retention
management of adverse events
unexpected challenges in data analysis
modifications to the analysis plan

18. Prevention is better than cure
A well informed DMC will often foresee potential issues before they arise and thereby avert damage to the trial

19. Educational and supportive role
What to present and not present in open session?
Who monitors safety day to day?
Prevention of SAEs (e.g. hepatic) through participant recognition of symptoms – modified consent forms to more clearly convey research related risk(s)
Recommendation re: management of AEs
Protecting the trial from inadvertent unblinding
Dialogue with trial team re: stopping rules
Membership of independent endpoint committee, who should be on – and who should not?

20. CONCORDE
The Anglo-French trial CONCORDE was the first phase III trial in HIV-infected persons to be conducted in the Europe; neither of the two DMC statisticians, Peter Armitage and Joseph Lellouch had had previous experience of trials in this area
The trial turned out to be particularly challenging for the DMC to monitor, notably because of concerns expressed by some of the investigators and the early stopping of a parallel trial, ACTG 019
Armitage subsequently recorded the experiences of the DMC along with important lessons that had been learnt
Armitage, Controlled Clinical Trials, 1999

21. FEAST: an unexpected outcome
In resource-rich countries, bolus fluid expansion is routinely used for the treatment of critically ill children
Interim results from FEAST showed an increased risk of mortality from bolus fluid expansion
The process whereby the DMC responded including its decision not to comment on protocol amendment increasing the bolus fluid administration which might have unblinded the study team have been described
Todd et al, Trials, 2013

22. Choose your DMC with care!
An experienced chair
Members who know the subject area
Critical friends
If invited consider carefully!
A place for learning?

23. Thank you!