1. The importance of randomisation in evaluation of treatments for Acute Myeloid Leukaemia Lessons from the UK NCRI AML16 and LI-1 trials
Ian Thomas, Senior Trial Manager
Centre for Trials Research, Cardiff University
Prof Robert Hills, Prof Nigel Russell, Dr Mike Dennis
Put all authors on and bold yourself.

2. Randomise or not: decision
Know your disease
Homogeneous/heterogeneous?
Outcome
Do you expect good or poor outcome?
Is the standard treatment suitable for randomisation?
Cheap, well-defined?

3. To not randomise? Single arm trials are Smaller, faster, cheaper
May be only option in a very rare disease
Valuable if outcome is known (e.g. no long term survival at all)
But what if your population is heterogeneous?

4. Case study: Pick a Winner
Numerous novel agents may be compared to standard treatment
Efficient design
Agents are compared within a randomisation arm against standard treatment
Robust data
Novel agents not compared against each other, or against ineligible control patients
Multiple ‘stand-alone’ trials within a trial
Early look at whether remission likely to be improved sufficiently

5. Non-intensive approach to AML
Findings from AML14
Low-dose cytarabine (ara-C) standard of care
Improved survival down to inducing remissions
However, no remissions in adverse risk patients
AML16 and LI1
Randomise novel therapies against low dose cytarabine
Look for improvement in survival
But if no improvement in remission, survival benefit unlikely

6. Pick a Winner history

7. Control arm outcomes Novel treatment CR rate (%)
1 year overall survival A
18%
24% B 8%
28% C
19% D
22%
30% E
26% F
25%
34% G
29%
27% H
31% I
33%
37%
NB Equivalent eligibility criteria

8. Scenario A new treatment has a remission rate of 22%
Compared to arms A, B, C, E this would be an improvement
But compared to arms D, F, G, H, I it would not be promising (null or worse)
Without knowing the patient details, we can’t interpret a single arm reliably

9. Conclusions
In poor-risk patients, estimate of outcome can be conducted early
With a proven surrogate for your outcome
In heterogeneous population, control arm may vary over time
Different eligibility criteria can be accommodated
Little option but to randomize in this AML population
Contemporaneous analysis is required
Phase II trial data may contribute to Phase III evaluation