Outcome measures
in clinical trials
Francesco Muntoni
Dubowitz Neuromuscular Centre
UCL Institute of Child Health
& Great Ormond Street Hospital
London, UK
Francesco Muntoni: disclosures
Duchenne
• CI of 3 AON clinical trials with AVI / Sarepta. Supported Sarepta in FDA
AdCom for eteplirsen
• PI of three Prosensa / Biomarin sponsored AON trials
• PI of PTC phase II and III sponsored trials. SAB in 2014, 2015 and 2016
• CI of Summit Phase I and II trials. SABs in 2013 and 2015
Spinal Muscular Atrophy
• PI of Trophos SMA III trial
• PI of ISIS antisense Phase III study
• PI of Roche phase I trial
(2013-14)
(2015), SAB in 2015 and 2016
(2016) (1 SAB in 2014)
• Others
• Member of Pfizer rare disease SAB since 3Q2014
• Italfarmaco, Akashi, Catabasis, Avexis ad hoc SAB member
Topics discussed
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Choice of efficacy outcome measures
Primary
Secondary
Exploratory
Surrogate endpoints
Primary outcome measures
• Scope: to tell if the drug is working, using a robust
and meaningful (especially for regulators) outcome
measure
Primary outcome measure
• Needs to be reproducible
• Needs to be sensitive to change
• Changes needs to be translatable in benefit
(minimally clinically significant difference, MCSD)
Secondary outcome measures
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Broadly speaking as the primary outcome measures
They capture different aspects of the disease
For example upper limb function
Coherence between primary and secondary outcome
measures VERY important in clinical trial design
Exploratory outcome measures
• Clinical trials give an unique opportunities to assess
how some measures could work better then current
gold standard, i.e. be more sensitive to therapeutic
response
-imaging (i.e. muscle MRI)
- serum biomarkers
Surrogate outcome measures
• An outcome measure that reasonably predicts the
outcome of the study drug.
• For example: Drugs that lower cholesterol are
approved if they lower cholesterol by X%, as we now
know well what is the correlation between x% of
cholesterol lowering and long term protection from
cardiovascular events.
Also consider differences between studies at
different stages
• i.e., in an early study, such as phase II study, often
exploratory measure very sensitive to any changes
are used, to get confidence on the new drug.
• Not necessarily the same outcome measure is used as
a primary outcome measure for the subsequent larger
studies in which the minimally clinically significant
difference plays an important role
Examples of primary outcome measures in current
clinical trials with perspective of regulatory
approval
• 6 minutes walk test
• 4 stair climb
Primary outcome measures
The NSAA also includes the possibility to record timed items (10 m timed walk/run
test and rise from the floor). The time taken to complete the task is not part of the
global score but provides an additional measure of the DMD boys’ abilities that
can be monitored over time.
Linearised scale
Exploratory outcome measures
Exon 53
• Muscle MRI
• Serum biomarkers
• Myotools
Moviplate
Key-pinch
Handgrip
Could dystrophin be considered as a surrogate
endpoint, in addition of being a pharmacodynamic
endpoint?
Parent Project Muscular Dystrophy e-mail to
community; September 19, 2016
Increased Dystrophin Detected in treated DMD
boys by 3 Methods
Absolute Differences
of Means
(Treated vs Untreated)
(% of Normal)
Fold
Increase
p-value
PDPF
+16.27%
15.5
<0.001
Intensity
+13.20%
2.4
<0.001
Western Blot
+0.85%
11.6
0.007
Method
• Dystrophin protein functionality suggested by
localization of dystrophin and associated proteins to
sarcolemmal membrane
• The unequivocal expression of dystrophin played
an essential role in the approval of eteplirsen
Concluding remarks
• It is important to recognise that the outcome measures need to be recognised
and agreed by regulatory authorities
• Different primary and secondary outcome measures can be used, also
depending on the mechanism of action of the drug
• There is an ongoing very constructive dialogue with regulatory bodies such as
EMA regarding what we can measure in DMD and what is the meaning of
different outcome measures
• Guidelines from EMA and FDA on trial design have been issued
• This is an area in rapid evolution, especially now that there are multiple trials
and drugs that have been approved and many others under development
• Some of the exploratory outcome measures could potentially become primary
measures once more information becomes available
Acknowledgment
Clinical and research team at
GOSH/ ICH