Egbert Biesheuvel, ASTERIX, spoke in the 'Current initiatives in rare diseases' panel at the Cambridge Rare Disease Summit 2015.

1. Advances in Small Trials dEsign for
Regulatory Innovation and eXcellence
Egbert
Biesheuvel
Nutricia
Research,
Utrecht
On
behalf
of
Kit
Roes,
Armin
Koch,
Martin
Posch,
Ferran Torres,
Hanneke vd Lee,
Cor
Oosterwijk,
Caroline
van
Baal
and
all
the
researchers
of
the
Asterix consortium

2. Outline
• Perspectives,
Patients and Evidence
• Concept
and
objectives
of
asterix
• Examples
of
progress
in
design
and
analysis

3. Perspectives, Patients and Evidence
Dependingon
definitions:
+/-­‐ 8000
rare
diseases
>
1000
new
therapies
designated as
orphan
90
orphan medicine
authorised (7
in
2013,
14
in
2014)
Authorised does
not automatically lead
to
available for patients
Perspective
of
market
authorisation of
a
new
drug
Evidence
based
decision of
allowing
physicians
to
add
a
new
drug
to
their
treatment
options
EMA
Orphan medicines
figures 2000-­‐2014

4. Perspectives, Patients and Evidence
In the
meantime I
passed away

5. Perspectives, Patients and Evidence
The
European
legislation
on
orphan
medicinal
products
[Regulation
(EC)
No
141/2000]
emphasises that
patients
suffering
from
rare
conditions
should
be
“entitled
to
the
same
quality
of
treatment
as
other patients.”
Currentrationale
is
to present
evidence at
the
sameconfidencelevels
Small
populations guidancedoes
stimulate alternatives for design
and
analyses
Carefulcase-­‐by-­‐case
decisions are
made,
that essentially may“relax”
level
of
evidence

6. Concept and objectives of asterix
• Unmet
need
for
drugs
to
treat
rare
diseases
• Difficulty
to
establish
efficient
and
reliable
evidence
from
clinical
trials
in
small
populations
• Absence
of
methods
to
include
patients
and
patient
perspectives to
generate
results
that
matter
to
patients
• Uncertainty
in
regulatory
decision
making
on
new
treatments

7. Patient
Think
Tank

8. Patient Think Tank
• Systematic involvement of
patients and their perspectives
• PTT
comprises of
12
members
Provide input
in
the
development of
methods to
• optimize use of
info
in
patient registries to decide on
trial
design
• include
patients
preferences
in
the
weighting
of
outcomes
• includepatient opinionson
novel trial
designs
1st F-­‐2-­‐F
meeting
in
October
2014
A’dam on
adaptive
designs
and
weighing
of
outcomes
2nd F-­‐2-­‐F
meeting
in
October
2015
Barcelona
on
Framework

9. Example: Framework for guidance
• Guidance on
design
at
disease level
no
longer practical
(over
8000
rare
diseases)
• One general document
(at
present)
may not provide
sufficient guidance
• Framework
with intermediate approach,
driven by key
characteristics of
disease and
treatment
Caridad Pontes,
Ferran Torres,
Josep Torrent et
al.

10. Proposed framework
Clinical
course
Acute
Chronic
Single
acute episode
Repeated acute
episodes
Slow/
Non
progressive
Progressive led
by
one system/organ
Progressive
multidimensional
multiorgan
Staged disease
Life threatening
Fulminating
Time
to
event
If SOC,
back to
normal
Repeated events
Predictable course
Clear-­‐cut episodes
Numer of
events,
time
Single
organ driven
Life-­‐long disease
Predictable course,
surrogates
SOC
generally available
Adults,
disabling
Multidimensional
single
organ
Patient reported outcomes,
QoL
Surrogates requiring validation
Children,
life lasting,
registries
Multidimensional
multiorgan
Patient/caregiver otucomes
Poor SOC
Poor prognosis
Subgroups required
Time
to
end-­‐points
Surrogates validated
Rareor
veryrare
Frequency
Ultrarare(<1/105)

11. Example: Multiple endpoints
• New
Fall back procedures
– Allow inference on
subsets of
endpoints
– Control
the
Family
Wise Error
Rate (Type
I
error)
– Can be designed to
be more
powerful,
taking joint
distribution (correlations)
into account
• Simulation studies
show
benefit,
also for small
sample
sizes
• Traditional
level
of
evidence
limits power
Robin
Ristl,
Martin
Posch

12. Example: Series of trials
• In
drug
developmentfor rare
diseases,
synthesisthrough
meta-­‐analysis
might improve robustnessof
(regulatory)
assesment
• Sequential meta-­‐analysis
can improve efficiency
of
drug
development plans
• Facilitating adaptive licensing
Armin
Koch,
Kristina Weber,
Ingeborg
van
der
Tweel,
Konstantinos
Pateras

13. Adaptive licensing
Eichler
et
al.,
Clin Pharm &
Therapeutics 2012;
91:
42-­‐37

14. Example: Series of trials
Initial idea:
• Bayesian
methods
for
extrapolation
in
rare
disease
• Reduce
the
burden
for
formal
proof
of
efficacy
Impact
on
decision
making
needs
to
be
fully
understood
• Frequentist
and
Bayesian
strategies
are
compared
from
a
decision
making
perspective
• In
case
of
2
(completed)
trials:
(1)
full
meta-­‐analysis,
(2)
one
trial
as
prior
for
the
other,
(3)
down-­‐weighing
the
first
trial

15. Concluding
• Innovationsin
design
possible
– but
more
complicatedto
comprehend
• Serious reconsideration of
level
of
evidence needed,
in
concert
with new
models of
decision making
• Framework
will help
to
provide guidance in
the
heterogenousworld of
rare
diseases
• Patient involvementis
essential
• We
have
just started…..