Michal kedar datal

1. Relievion - Clinical strategy
November 14th, 2016
Dr. Shany Blum – VP Clinical Development Service

2. Overview
• A medical device submitted for CE certification need
to be accompanied besides the technical file also
with a Clinical Evaluation Report (CER)
• Clinical data acquired for a medical device need to
comply with ISO 14155 and MEDDEV 2.7.2 rev 2.
• If an equivalent device marketed in the EU can be
determined then the CER may use literature search
approach. In case there is no equivalent device the
sponsor need to provide clinical data resulting from
a clinical investigation.
• The study design and data should support the
intended use and indication for use of the device.

3. Protocol 100CLD
• The protocol defines the investigational device as
Cefar Primo Pro manufactured by DJO LLC. It holds
FDA clearance since 2002 (under 510k number
k020803), CE (Complies with MDD 93/42/EEC
requirements, Notified body Intertek ETL Semko
0413) and Israeli AMAR certification.
• This is not Neurolief’s device. Was any amendment
done to describe Neurolief’s device?
• The CSR refers a description of device similar to the
current design of Relievion.
• The protocol is overall well written and according to
GCP and same is the CSR.

4. Protocol 100CLD
• The study was powered to see a 20% effect size
difference between active and placebo for a sample
size of 40 subjects (20 active and 20 placebo). Only
30 subjects (15 in each arm) completed the protocol
and were evaluable. This may jeopardize the study
power which need to be recalculated to evaluate the
validity of the results.
• The “Placebo” arm is not appropriate, administering
no electrical current cannot be considered as
placebo hence the study cannot be considered as a
blinded study.
• Overall good safety was observed.

5. CE – using Protocol 100CLD results in a
success oriented approach
• Several shortcomings of the 100CLD study need to
be overcome.
• For the CER we can use the study data assuming
found valid and refer that as a study done with a
device identical in terms of output to the current
design of Relievion.
• Due to the smaller sample size and the fact that the
treatment was provided by a clinician rather than
self administration home use we will need to provide
a bridge study that will also include elements of
usability in addition to a formal usability study.

6. CE – using Protocol 100CLD results in a success
oriented approach
• Assuming similar effect size to the one observed in
study 100CLD a sample size of 10 active subjects
will be sufficient. In order to allow usability
elements at least 15 subjects need to be enrolled
and treated. This bridge will be planned to
recapitulate the effect seen in study 100CLD and
we will claim that a placebo is not required. The
study protocol will be similar to 100CLD protocol
but the treatment will be self administered in the
home setting.
• A formal Usability study should also be performed
with 15 users.

7. CE with gen 2 device
• We can use protocol 100CLD results as part of the
clinical evaluation of the device.
• A clinical trial with 70 migraine patients, assuming
25% effect size in the active vs. 10% at the sham (35
active and 35 sham) should be conducted. The
treatment should be a self home treatment.
Duration of the study might be similar to 100CLD or
maybe add 1-2 additional “migraine attacks”.
• Usability study should also be conducted with 15
users.

8. FDA
• A clinical trial with 160 migraine patients, assuming
20% effect size in the active vs. 10% at the sham (80
active and 80 sham) should be conducted. The
treatment should be a self home treatment.
Patients should be treating migraine attacks over 3
months following a one month run-in period. The
number of treated attacks can be limited but not
less than 3 overall treated attacks*.
• Usability study should be conducted with 15 users.
*design is similar to Cefaly and eNeura