at ICH Presented by Rob Hemmings Problem statement Lack of clarity in trial objectives Potential to confuse developers and decision makers Misleading information to patients and prescribers ID: 591733
Download Presentation The PPT/PDF document "Estimands" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Estimands at ICH
Presented
by Rob HemmingsSlide2
Problem statement
Lack of clarity in trial objectives:
Potential to confuse developers and decision makers.
Misleading
information to patients and prescribers
So
many conversations about HOW to estimate treatments effects, and so few about WHAT to
estimate.
The HOW has determined the WHAT.
WHAT do we want to estimate?Slide3
Context
Patients differ in response to treatment.
Some patients will tolerate a medicine and adhere to its administration schedule, others will not;
Some patients will require additional medication, others will not.
Some patients die.
More
than one
treatment effect
can be described and estimated
.
Are these ‘
intercurrent
events
’ problems for estimation of a ‘true’ effect or are they to be embraced?Slide4
Current practice under ICH E9
E9 introduces
the ITT principle as the best way to assess a
‘treatment-policy’.
‘Treatment discontinuation’ has been conflated with ‘Trial discontinuation’.
Data after treatment discontinuation or perhaps use of rescue medication is not collected / not used. Multiple
problems have been labelled as
‘missing
data
’.
Today’s
practice doesn’t
adhere to the ITT principle. It
hasn’t been clear
WHAT treatment
effect is then being estimated, and
arguably estimators (HOW) do not fully respect
randomisation
.
Can
we answer questions other than treatment-policy whist maintaining the benefits of
randomisation
?Slide5
ICH E9 (R1)
Estimands
;
we have
these
NOW, in every trial, we just don’t talk about
them.
ICH
E9 addendum is currently being developed to provide a structured framework for talking about WHAT to estimate = the
estimand
.
Statistical approaches
then need
be aligned with the treatment effect of
interest.
How to write a document that fits all therapeutic and
experimental
conditions?Slide6
ICH E9 (R1) … work continues …Slide7
Trial
Objective
Estimand
Main
Estimator
Main
Estimate
Sensitivity
Estimator
1
Sensitivity
Estimate
1
Sensitivity
Estimator
k
Sensitivity
Estimate
k
…
…
Target of
estimation = WHAT
Method of
estimation = HOW
Sensitivity analysis
Framework I
Supplementary
analysis
Choice of
estimand
may impact study design and conduct and needs to be discussed first.Slide8
Estimand attributesSlide9
Strategies
At least 5 strategies for
addressing
intercurrent
events e.g. the
intervention
effect
“regardless
of switching to rescue
medication”.
Determine which
intercurrent
events need to be considered explicitly in the construction of the
estimand in order to give a clear understanding of the treatment effect to be estimated.Multiple intercurrent
events per trial means multiple strategies per estimandE.g.
Difference
between mean change from baseline to week 24 in HbA1c in the target
population, regardless of adherence, if rescue medication is not availableSlide10
Construction of an estimand
Should be:
consequent
to the trial objectives and should precede choices relating to data collection and analytic approaches.
clinically interpretable, in terms of the population and endpoint, but also in terms of the intervention effect of interest and, finally, the summary measure.
duly justified considering the therapeutic setting and the treatment goals of the intervention, from which the key scientific questions of interest can be derived.
a multi-disciplinary undertaking and should be the subject of discussion between sponsors and regulators.Slide11
Impact: regulatory experience
Current experience from Scientific Advice Working Party
Company questions
Plenary discussions
Future
expectations for Scientific Advice requests
Identify
intercurrent
events, discuss strategies and resulting
estimands
Move
away from discussing endpoints?
Discuss
design and statistical analysis in relation to an agreed
estimand
Slide12
Impact: regulatory experience
Current experience from
CHMP
List
of Questions; ask about the handling of ‘missing data’ or treatment effect of interest?
Plenary
discussions
Potential consequences for
future
MAAs
One
‘
estimand
’ or many?
Product Information and HTA engagement
Note on external comparisons; ‘context’; meta-analyses etc
.
Current expectations for future therapy-area guidelinesSlide13
Thanks for your attention