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Acta Neurol Scand DOI: 10.1111/ane.12287

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

ACTA NEUROLOGICA

SCANDINAVICA

Drug-resistant MS spasticity treatment with

Sativex add-on and driving ability

Freidel M, Tiel-Wilck K, Schreiber H, Prechtl A, Essner U, Lang M.

Drug-resistant MS spasticity treatment with Sativex

add-on and

driving ability.

Acta Neurol Scand: DOI: 10.1111/ane.12287.

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Objective –

The aim of the present observational study was to

determine the effects of a delta-9-tetrahydrocannabinol (THC) and

cannabidiol (CBD) oromucosal spray (Sativex

spray), brand name

Sativex

, indicated for drug-resistant MS spasticity, on the driving

ability of treated MS patients.

Methods –

The study was conducted

over a period of 4–6 weeks. Thirty-three MS patients with moderate

to severe treatment-resistant spasticity and planned to begin add-on

treatment with Sativex

were enrolled at three specialized MS centres

in Germany. A set of ﬁve driving test procedures from a validated

computerized test battery was used to evaluate the driving ability of

eligible patients. Tests were performed by patients at baseline and

repeated after 4–6 weeks of treatment with Sativex

oromucosal

spray. According to German normative data, the test thresholds

achieved by the general population served as a reference to allow for

a ﬁtness/unﬁtness to drive classiﬁcation.

Results –

Patients showed

comparable driving test results at baseline and at ﬁnal visits. Only two

patients changed classiﬁcation shifting from ‘unﬁt’ to drive to ‘ﬁt’ and

vice versa. The mean severity of spasticity, as self-reported by the

patients, improved with statistical signiﬁcance. Sativex

was generally

well tolerated.

Conclusions –

Treatment of MS patients with Sativex

does not negatively impact on driving ability and may improve

moderate to severe treatment-resistant MS spasticity.

M. Freidel

, K. Tiel-Wilck

H. Schreiber

, A. Prechtl

U. Essner

, M. Lang

NTD Study Group, NeuroPraxis

–

MS-Zentrum,

Kaltenkirchen/Holstein, Germany;

NTD Study Group,

NeuroTransData GmbH, Berlin, Germany;

NTD Study

Group, NeuroPoint Studienzentrum, Ulm, Germany;

Almirall Hermal GmbH, Reinbek, Germany;

O. MEANY Consultancy GmbH, Hamburg, Germany

Key words: MS spasticity; tetrahydrocannabinol/

cannabidiol; computerized test battery; driving ability

U. Essner, O. MEANY Consultancy, Ohkamp 26, 22339

Hamburg, Germany

Tel.: +40 5000 383

e-mail: [email protected]

Accepted for publication July 10, 2014

Introduction

Multiple sclerosis (MS) is the most common

chronic inﬂammatory disease of the central ner-

vous system (1). A wide range of symptoms

appear at onset and during progression (2). MS

spasticity (muscle rigidity, spasms) affects up to

80% of patients and is one of the most common

and disabling symptom (3). It impacts signiﬁ-

cantly on patients’ quality of life (4). Suffering

from moderate to severe spasticity does not only

impair mobility, social life and activities of daily

living but may also be associated with additional

complications such as pain, sleep disorders,

depression and skin damage (5).

The number of MS disease-modifying treatment

options has expanded in recent years. Nevertheless,

for MS spasticity symptomatic treatment, a com-

bined

delta-9-tetrahydrocannabinol/cannabidiol

oromucosal spray (Sativex

; GW Pharma Ltd.,

Salisbury, UK) is the only approved drug speciﬁ-

cally developed to treat MS spasticity in recent

years. Sativex

is indicated as an add-on therapy

for patients suffering from moderate to severe

MS spasticity resistant to previous pharmacologi-

cal interventions. The drug has recently been rec-

ommended in the German Guideline for the

treatment of MS spasticity (6).

Several clinical trials have investigated the efﬁ-

cacy and safety of Sativex

and demonstrated a

clinically relevant beneﬁt for MS patients suffer-

ing from spasticity (7–11). These data were con-

ﬁrmed by long-term studies (10, 12–14).

According to the studies mentioned above,

Sativex

was well tolerated. Treatment-related

adverse events with a higher incidence in the

active treatment group compared to the placebo

group were as follows: dizziness (32% vs10%),

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Freidel et al.

fatigue (23% vs 16%), somnolence (14% vs 4%),

nausea (14% vs 5%), vertigo (11% vs 4%) and

asthenia (13% vs 6%) (8). The tolerab-

ility of Sativex

was also analysed in several

systematic reviews (10, 15, 16). The adverse eve-

nts are most often described as mild or moderate

(8, 10, 17). The most frequent reported adverse

events during a longitudinal/follow-up study in

which patients received up to 2 years Sativex

were oral pain (20%), dizziness (15%), diarrhoea

(12%) and nausea (11%), mostly described as

mild or moderate. Only 17/137 patients discontin-

ued the study due to adverse events (10,18).

Despite the potential of cannabinoids to nega-

tively impact on cognitive functions of MS patie-

nts, the rate of reported motor vehicle accidents

has not increased under cannabinoid medication

use (17).

Until now, the ongoing GW EU Sativex

reg-

istry has collected data regarding tolerability and

safety of Sativex

from more than 680 patients

with an average follow-up time of 570 days.

In this registry, a questionnaire with speciﬁc

questions concerning driving ability was applied

(19, 20). According to these data, no signs of

deterioration of driving ability were reported by

any of the patients. Nevertheless, there is great

interest to further clarify the putative impact of

Sativex

on patients driving abilities and to allow

physicians to advise their patients regarding any

potential risks.

This pilot, prospective, multicentre and non-

interventional study was conducted to collect

data on driving ability, tolerability and safety

from patients starting Sativex

treatment under

real-life conditions.

Methods

Patient population

Exclusion:

1. Any condition or shortcomings in their knowl-

edge of national language, suggesting that the

driving ability tests were not to be fully under-

stood, and/or patient questionnaires could not

be completed.

Due to the nature of a non-interventional study,

there were no other speciﬁc selection criteria

regarding restrictions on concomitant medication.

Contraindications and warnings were followed as

stated by the approved Sativex

Summary of

Product Characteristics (SmPC).

Investigational product and dosing

The investigational product is a cannabinoid-

based oromucosal spray medication distributed

under the brand name Sativex

, which contains

the active substances delta-9-tetrahydrocannabi-

nol and cannabidiol at an approximate ratio of

1:1 and is applied directly to the mucosa of the

oral cavity. Importantly, the drug is licensed as

add-on therapy to patients’ current antispasticity

medication. As recommended by the SmPC,

patients follow a 2-week dose titration phase dur-

ing which the most active and tolerable dose is

determined through gradual titration. The maxi-

mum daily dose of Sativex

allowed was

12 sprays/day.

Study design

It was intended to recruit at least 30 MS patients

suffering from moderate to severe treatment-resis-

tant spasticity over a period of 6 months by three

ambulant German MS specialist centres. Main

selection criteria

Inclusion:

1. MS patients

≥18

years, suffering from moder-

ate to severe MS spasticity and who did not

respond adequately to other antispasticity

medication.

2. Patients who drive a vehicle at least once a

week.

3. Signed informed consent.

4. Decision to start Sativex

treatment made

prior to study enrolment.

The study was designed as a pilot, prospective

and post-marketing surveillance study over a per-

iod of 4–6 weeks.

Besides anamnestic data, the results from base-

line and ﬁnal visit driving ability tests, as well as

data concerning the efﬁcacy and safety of the Sat-

ivex

treatment, have been documented.

Driving ability tests were performed at the start

of the treatment and at a follow-up visit

4–6 weeks later, when physicians examined

whether the patient had responded to the new an-

tispasticity treatment.

At baseline sociodemographic data and infor-

mation about patients’ MS, such as MS type,

symptoms, MS spasticity, treatment with antisp-

astic and/or other concomitant drugs, were docu-

mented. Expanded Disability Status Scale (EDSS)

(20) scores at baseline were compared to a refer-

ence score 12 months earlier to monitor MS dis-

ease progression. In addition, the number of MS

relapses 12 months prior to the study were deter-

mined. Information regarding severity of MS

spasticity was collected through a validated and

SUU, Alm.del - 2014-15 (1. samling) - Bilag 111: Henvendelse af 20/11-14 fra Benjamin Müller vedr. nyt Sativex-køreevnestudie

Sativex

and driving ability

patient-rated outcome measure, a 0–10 numeric

rating scale (NRS), at baseline and ﬁnal visit

(21). In addition, results from speciﬁc driving

ability tests and the Epworth 8-item Daytime

Sleepiness Scale (ESS) (22) were also collected at

baseline and ﬁnal visit. Adverse events were

reported throughout the study.

An ethics approval for this study was obtained

by the Freiburg Ethics Commission International

(FEKI), feci code: 012/1343.

Data management and statistical analysis were

€

performed by ANFOMED GmbH (Mohrendorf,

Germany).

Driving tests

minimum percentile rank of 16% in each of the

ﬁve different categories of the driving ability test.

A test score lower than 16% means that a sub-

ject performs below the bottom sixth of the com-

mon population, independently of age.

Importantly, in real-life conditions, German

driving guidelines are ﬂexible within the classiﬁca-

tion ‘ﬁt’ for driving if:

1. Values below 16% are situation speciﬁc (situa-

tional),

2. Values below 16% in one test are compensated

by stable performances in other tests,

3. There are other procedures which indicate

(allow for) reasonable compensation of deﬁcits

(anticipation, risk awareness and caution),

4. The driver gains credit for having already pro-

ven herself/himself in practice.

The participants’ driving ﬁtness in this study

was deﬁned by use of two different approaches.

The ﬁrst approach required patients to score a

minimum percentile rank of 16% in each of the

ﬁve tests in order to be classiﬁed as ‘ﬁt to drive’.

The second approach followed the German nor-

mative ﬂexibility frame and allowed for ‘ﬁt to

drive’ classiﬁcation of patients scoring below

16% in one or more test when low performance

was compensated by a minimum score of 50% in

another test.

MS spasticity rating scales

Following German guidelines (23), a computer-

ized and validated test battery Schuhfried-Wie-

ner Testsystem was used to assess driving

ability. The test battery offered by Schuhfried

GmbH (24) consists of ﬁve different test catego-

ries, each of which measures a different dimen-

sion including reaction speed, concentration,

orientation, stress tolerance and attention. With

test duration of 6–14 min per category, an

entire test session lasted about 45 min. The indi-

vidual reaction time was measured by the motor

speed reaction test (RT), which assesses basic

attention (vigilance) and response (reaction time

deﬁned as the time that elapses between a signal

and the start of a tested person’s mechanical

response movement).

Concentration was tested by the concentration

cognitrone test (COG), which measures the mean

reaction time between a complex (bimodal) signal

(simultaneous appearance of yellow light and

tone) and the response by mechanical movement.

Besides time measurement (reactions times), tasks

need to be solved as a decisive criterion of this

test (85% of the requested tasks are normally

solved).

The visual pursuit test (LVT) measures visual

orientation facing simple structures in a complex

environment.

The stress tolerance determination test (DT)

measures attention and individual reaction time

in situations requiring continuous, swift and vary-

ing responses to rapidly changing visual and

acoustic stimuli.

Finally, the adaptive tachistoscopic trafﬁc per-

ception test (ATAVT) assesses visual observa-

tional ability and skill in obtaining an overview

as well as perceptional capacity to react in spe-

ciﬁc situations.

To be classiﬁed as ‘ﬁt for driving’, ofﬁcial test

thresholds require an individual to score a

The severity of MS spasticity was assessed by the

patient through the validated 0–10 NRS (22).

Patients were asked to indicate their current level

of spasticity ranging from ‘no spasticity (NRS

0)’

to the ‘worst spasticity imaginable (NRS

10)’. In

addition, the physician rated the level of spasticity,

by selecting one of the following categories: mild

(occasional impact on activities), moderate (fre-

quently affects activities) or severe (patient is

forced daily to modify activities) (3).

Adverse events

Adverse events were documented at the ﬁnal

visit.

Statistical analysis

Computation of mean values and standard devia-

tion, median, lower and upper quartiles and list-

ing of minimum and maximum values was

performed for quantitative variables, as well as

calculation of frequencies for nominal and ordinal

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Freidel et al.

variables. Tests for signiﬁcance (signed rank test)

were computed for driving tests and level of spas-

ticity severity, but should only be interpreted in a

descriptive exploratory way.

P-values

reported are

two-tailed, and an alpha level of 0.05 was used to

assess statistical signiﬁcance. No correction for

multiple testing was performed.

The ﬁve tests procedures (LVT, COG, DT, RT

and ATAVT) were analysed as percentile ranks.

The percentile rank of a particular test allows to

ascribe the percentage of examinees in the norm

group who scored below threshold score (24).

Results

Demography and baseline characteristics

their spasticity at baseline, including baclofen

(nine patients), tolperisone (nine patients),

gabapentin (ﬁve patients) and tizanidine (three

patients) (multiple prescription possible). Con-

comitant diseases were documented in 11 patients

(33.3%), the majority with epilepsy (9.1%), fol-

lowed by hypertension, pain, migraine, osteoar-

thritis and restless legs syndrome (all at 6.1%).

Seven of these patients (21.2%) received addi-

tional medication for these treatment of these dis-

eases (for example, pramipexol, tramadol and/or

non-steroidal anti-inﬂammatory drugs).

Exposure to study medication

Thirty-three patients were enrolled in the study,

which started in June 2012 and was completed in

April 2013. Patients’ ages ranged from 33 to

68 years, implying a mean age of 48.1 years.

More female (60.6%) than male (39.3%) subjects

were recruited, reﬂecting the epidemiology of MS

in the general population.

Most patients (63.6%) suffered from secondary

progressive MS and, on average (ÆSD), patients

were diagnosed with MS 11.5 (Æ6.8) years prior

to enrolment into the study. More than 90% of

all patients presented with additional MS symp-

toms such as fatigue, depression and bladder

disorders being among the most common symp-

toms. On average, spasticity had been present for

6.7 (Æ5.4) years. EDSS scores were collected from

all patients at baseline with an average score of

4.6.

Multiple sclerosis was treated with immune

modulators in 22 participants (66.7%). Twenty-

six patients (78.8%) received physiotherapy and

13 (39.4%) received pharmacological therapy for

The mean duration of the observational period

was 5.3 weeks. Two patients (6.1%) stopped

treatment prematurely; one non-responder and

one due to intolerance. Thirty-one subjects

(93.9%) completed the study according to sche-

dule. The mean dose of Sativex

at the end of

the study was 5.1 sprays per day.

Driving tests results

A total of 31 patients completed all ﬁve driving

tests at both baseline and ﬁnal visit. Compared to

baseline, none of the driving tests indicated a sta-

tistically signiﬁcant deterioration of patients’ per-

formance at ﬁnal visit. Interestingly, stress

tolerance (DT) improved considerably and was

statistically signiﬁcant (P

0.026; Fig. 1).

According to the strict criterion for evaluating

driving ability, a person was only considered ‘ﬁt’

for driving if a percentile rank of at least 16%

was achieved in each of the ﬁve subscores (tested

areas). According to this analysis, only 14 of the

31 patients analysed (45.2%) proved ﬁt for driv-

ing at baseline (Table 1a).

Figure 1.

Driving ability tests, differences baseline/ﬁnal visit.

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Sativex

and driving ability

Table 1

Fitness for driving at baseline and final visit, number and percentage

of patients classified

‘fit’

‘unfit’

for driving (a) according to the strict criterion

(surpassing 16% threshold in all tests) and (b) using modified criterion

NRS and effectiveness on MS spasticity

Severity of spasticity within the past 24 h was

self-rated by patients using the 0–10 NRS. The

average score decreased, and therefore spasticity

improved, by 2.4 points from 6.0 points at base-

line to 3.6 points at ﬁnal visit (Fig. 2). This

change was highly statistically signiﬁcant

0.0001) and clinically relevant (21).

Comparison of severity of spasticity levels

showed that spasticity improved during the study.

At baseline seven (21.1%) patients suffered from

severe spasticity, and at the end of the study, only

one patient (3%) was severely affected (Fig. 3).

Safety

number of patients; grey area: test results with no change from fit to unfit

(and vice versa) at final visit in comparison to the beginning of study; stripes hor-

izontal: test results with change from unfit to fit at final visit in comparison to

the beginning of study; stripes vertical: test results with change from fit to unfit

at final visit in comparison to the beginning of study.

The second ﬂexible approach allowed for a ‘ﬁt

to drive’ classiﬁcation of patients that scored

below 16% in one or more tests when low perfor-

mance was compensated by a minimum score of

50% in another test. When this approach was

applied, 24 tested subjects (77.4%) proved ﬁt for

driving at baseline, while seven (22.6%) did not

(Table 1b).

Upon treatment with Sativex

, two patients

(6.5%) changed categories from ‘ﬁt’ at baseline to

‘unﬁt’ at ﬁnal visit, and vice versa (Table 1b).

Therefore, frequencies of patients classiﬁed as ‘ﬁt’

or ‘unﬁt’ did not change during the study. In

summary, treatment of patients with Sativex

did

not show deterioration of patients’ ability to

drive.

In total, ﬁve non-serious adverse events occurred

in four patients. These were dizziness in two

patients (6.1%), and ligament sprain, thrombosis

and a vertigo episode in one patient (3.0%),

respectively. All of these events were considered

mild or moderate. Three events were considered

drug related (dizziness and vertigo). All patients

had recovered by the end of the study. One

patient discontinued prematurely due to adverse

events (dizziness and vertigo). Moreover, the dose

of Sativex

therapy was reduced in one case due

to dizziness.

Discussion

Currently, profound knowledge concerning the

effects of delta-9-tetrahydrocannabinol/cannabidi-

ol therapy on individuals‘ driving ability is

still lacking. Therefore, patients experiencing side

effects such as dizziness and somnolence upon

Figure 2.

Level of spasticity at baseline and ﬁnal visit that patients (n

33) have experienced over the past 24 h (0

no spastic-

ity, 10

worst spasticity imaginable; X

mean,

median, []

interquartile, -

minimum and maximum).

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Freidel et al.

Figure 3.

Percentage of patients with mild, moderate and severe spasticity at baseline and ﬁnal visit.

treatment initiation are often advised not to drive

or operate machinery, as physicians are required

by duty of care to provide driving advice to

patients with certain conditions (25). However, a

survey revealed that patients with neurological

conditions receive inconsistent advice on driving

from their doctors. Moreover, only 61% of MS

patients received advice (25).

A possible reason may be the fact that speciﬁc

evidence from clinical trials on driving ability is

currently lacking. This holds also true for the

effects of delta-9-tetrahydrocannabinol/cannabidi-

ol therapy on individuals‘ driving skills. There

are only a few general studies investigating the

driving ability of MS patients. A previous com-

puter-test based study on 15 MS patients suffer-

ing from mild to moderate symptoms of MS

showed no differences between healthy controls

(17 persons) and patients with MS on all mea-

sures of the primary driving task, but MS

patients performed worse in the divided response

time and accuracy tests (26). Another study

showed that MS-associated cognitive and physical

impairments might increase the risk for car acci-

dents (27).

Driving is not contraindicated for other

approved medications with similar pharmacology

and safety proﬁles to Sativex

(such as Nabilone

or Dronabinol), but a warning is given to avoid

driving or operate machinery if somnolence, diz-

ziness or related adverse events are perceived.

Importantly, various RCTs have proven that

MS patients beneﬁt from cannabinoid therapy

(2, 7–9, 12, 15). These trials reported a reduction

in the severity of spasticity and associated symp-

toms, which result in an improved ability to per-

form daily activities (2, 4). Furthermore, patients

who had been resistant to other therapies did

beneﬁt from treatment with Sativex

(2, 4).

The present pilot study aimed to examine

whether Sativex

may impair driving ability of

MS patients. From a general view, there was no

difference in the number of patients considered ﬁt

or unﬁt to drive before and after Sativex

use,

which suggests that Sativex

does not impair

driving ability. Also according to the individual

driving tests used for our study, Sativex

treat-

ment does not impair patients’ ability to drive.

Naturally, no practical on-road test was per-

formed for our study as the use of the modern

computerized test systems have previously been

proven to be a standardized, accurate and com-

prehensive tool (28–30). These studies demon-

strated an excellent correlation between test

results and patients’ on-road performance, with

more than 80% accuracy for the stroke driver

screening assessment and more than 90% accu-

racy for the useful ﬁeld of view test (28).

Interim data of safety registries in UK and

Spain, which contain data on driving ability, have

not reported any new safety/tolerability concerns

after 1 or more years of treatment with Sativex

(17). Moreover, there was no evidence indicative

of impaired driving ability as well as no relevant

incidence cases or other aspects of concern such

as psychiatric or nervous system events (18).

Importantly, the rate of reported motor vehicle

accidents has not increased on Sativex

exposi-

tion, and no obvious incidents have occurred in

the post-marketing experience so far (31).

Within the current legal framework, an expert

decides about patients’ ability to drive on an indi-

vidual basis. This potentially allows some people

to legally drive although they might fail a driving

ability test. This situation is reﬂected by the

results of our study. When patients were assessed

according to the strict driving criteria

–

referring

to the requirement to meet the 16% percentile

rank threshold at baseline in all subtests

–

only

45.2% of enrolled MS patients were classiﬁed ‘ﬁt

for driving’ at the beginning of the study,

whereas 54.8% were classiﬁed ‘unﬁt’ for driving.

When patients were assessed according to the

operative modiﬁed ﬂexible criterion, 77.4% of the

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Sativex

and driving ability

patients were classiﬁed ﬁt for driving, which

would still leave more than one-ﬁfth of the evalu-

ated patients ofﬁcially unable to drive. This sug-

gests that a certain percentage of active drivers

among MS patients seem to be in fact unﬁt for

driving. It cannot be excluded that possible

changes in the concomitant diseases and/or con-

comitant medications such as tramadol, pramip-

exol or ß-blockers could have had an inﬂuence

on driving ability.

In sum, the present study suggests that driving

skills are not impaired by treatment with Sati-

vex

. The present study has some limitations that

should be considered in interpreting the data.

The sample size was quite small to generalize the

data. Further, long-term studies including more

patients, such as speciﬁc cohort studies, are

required to fully deﬁne the aspect of road safety

under treatment with Sativex

Acknowledgments

First of all, the authors would like to thank all participating

patients and the study nurses who provided very valuable

help with performing the driving test sets. Further the

authors would like to thank Tanja Burkard from Anfomed

GmbH, Germany, for the execution of the study, the analy-

ses and the preparation of the draft manuscript.

012/1343) and have therefore been performed in accordance

with the ethical standards laid down in the 1964 Declaration

of Helsinki and its later amendments.

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Conﬂict of interest

M. Freidel has received personal compensation for activities

with Almirall, Bayer Schering, Teva, Merck Serono, Biogen

Idec, Novartis, Sanoﬁ Aventis, Genzyme, Mundipharma

and Medtronic. U. Essner received consultancy fees from

Almirall Hermal GmbH, Carem GmbH, O. MEANY

DM&PM GmbH and Teva GmbH. K. Tiel-Wilck received

honoraria for lectures, studies and consultancy from Almir-

all Hermal GmbH, Bayer-Schering Pharma, Biogen Idec,

Genzyme, Ipsen Pharma, Merck-Serono Pharma, Merz

Pharma, Novartis AG, Roche Pharma, Sanoﬁ Aventis and

TEVA. A. Prechtl is Director of Medical affairs of Almirall

Hermal GmbH. H. Schreiber has received research grants

from Bayer AG, Biogen Idec and Teva; has received travel

grants and honoraria for serving as a speaker at scientiﬁc

meetings and as a member of scientiﬁc advisory boards for

Almirall, Bayer AG, Biogen Idec, Merck, Novartis & Teva.

M. Lang received compensation for talks and funding for

studies from Biogen-Idec, Bayer, Novartis, Serono, Teva,

and Genzyme.

Source of funding

The study was sponsored by Almirall S.A., Barcelona, Spain.

Ethical standard

All patients provided informed consent. The study was

approved by the ethical committee in Germany (Freiburg

Ethics Commission International (FEKI), under the feci code:

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