디지털 치료제, 또 하나의 신약

디지털 치료제, 또 하나의 신약
디지털 헬스케어 파트너스

대표파트너

최윤섭, PhD

“치료 효과가 있는 ‘게임’이 아니라,

‘치료제’가 (어쩌다보니) 게임의 형식을 가진 것이다”

by Eddie Martucci, CEO of Akili Interactive, at DTxDM East 2018

5www.dtxalliance.org
Defining Digital Therapeutics
Thought leaders across the digital therapeutics industry,
supported by the Digital Therapeutics Alliance, collaborated
to develop the following comprehensive definition:
Digital therapeutics (DTx) deliver evidence-based
therapeutic interventions to patients that are driven by
high quality software programs to prevent, manage,
or treat a medical disorder or disease. They are used
independently or in concert with medications, devices,
or other therapies to optimize patient care and health
outcomes.
DTx products incorporate advanced technology best
practices relating to design, clinical validation, usability,
and data security. They are reviewed and cleared or
approved by regulatory bodies as required to support
product claims regarding risk, efficacy, and intended use.
Digital therapeutics empower patients, healthcare
providers, and payers with intelligent and accessible tools
for addressing a wide range of conditions through high
quality, safe, and effective data-driven interventions.
Digital therapeutics
present the market
with evidence-based
technologies that
have the ability to
elevate medical best
practices, address
unmet medical needs,
expand healthcare
access, and improve
clinical and health
economic outcomes.
• 질병을 예방, 관리, 혹은 치료하는 고도의 소프트웨어 프로그램
• 독립적으로 사용될 수도 있고, 약제/기기/다른 치료제와 함께 사용될 수 있음
• 효능, 목적, 위험도 등의 주장과 관련해서는 규제기관의 인허가를 거침
Digital Therapeutics Alliance (DTA) white paper, 2018

대표적인 디지털 치료제 사례연구
• Pear Therapeutics
• Akili Interactive
• Click Therapeutics
• Dthera Science
• Noom, Omada Health
• Hurray Positive, SK Health Connect
• Virtual Vietnam
• AppliedVR
• Woebot
• Cognoa
• Propeller Health
• Neofect

•의사의 ‘처방’을 받아, 12주에 걸쳐 알콜, 코카인, 대마 등의 중독과 의존성을 치료

•스마트폰 앱 만으로 치료용 FDA 인허가 (De Novo)를 받은 것은 최초 (2017년 9월)

DE NOVO CLASSIFICATION REQUEST FOR RESET
logistic Generalized Estimating Equations (GEE) model with factors for treatment, time
and treatment X time (“treatment times time”) interaction. Missing data were treated as
failures. The analysis results of abstinence for cohort 1 and 2 are presented below,
additionally compared by abstinence at baseline. The abstinence analyses were
completed in the context of a GEE model that incorporates within-subject variability
across the observation window and estimates abstinence at specified time points based on
the model the analyses yields percentages rather than absolute numbers. The number of
patients reported in the table below represents the number of patients in that entire group
(e.g., N=252 patients in Cohort 1 were in the TAU group overall; N=139 patients were
abstinent at baseline in the Cohort 1 TAU group).
Table 3: Abstinence rates in Cohorts 1 (N=507) and 2 (N=399)
Patients who received rTAU + reSET had statistically significant increased odds of
remaining abstinent at the end of treatment:
Cohort 1: Odds ratio=2.22, 95% CI (1.24, 3.99); p=0.0076
Cohort 2: Odds ratio=3.17, 95% CI (1.68, 5.99); p=0.0004.
Cohort 3 (all opioids excluded, N=153 TAU, N=152 rTAU+reSET) had similar
abstinence to cohorts 1 and 2, with abstinence rates in the rTAU + reSET arm of 38.5%
compared to 17.5% in the TAU arm (Odds Ratio=2.95, 95% CI=1.43, 6.09, p=0.0034).
Abstinence: patients who were abstinent at baseline: Patients who were abstinent at
baseline were significantly more likely to remain abstinent throughout the study than
patients who were not abstinent at baseline for both patients who received TAU and
patients who received rTAU + reSET.
•대조군 대비 통계적으로 중독 치료 효과에 유의한 차이
reSET의 임상 시험 결과

reSET의 임상 시험 결과
DE NOVO CLASSIFICATION REQUEST FOR RESET
The Kaplan-Meier curve for cohort 1 is shown below:
Figure 2: Kaplan-Meier curve for Cohort 1 (all comers)
Adverse events
In the entire clinical study, the number of patients with any adverse event was 13% (n=66). The
number of patients with any event was 29 (11.5%) in TAU and 37 (14.5%) in reSET + rTAU (p
= 0.3563). None of the adverse events in the reSET arm were adjudicated by the study
investigators to be device-related. The events evaluated were typical of patients with SUD,
including cardiovascular disease, gastrointestinal events, depression, mania, suicidal behavior,
•12주 치료 이탈율에도 통계적으로 유의미한 차이 확인

대표적인 Digital Therapeutics의 사례연구
• Dthera Science
• Virtual Vietnam
• AppliedVR
• Woebot
• Cognoa
• Neofect

새로운 개념의 제약회사?

ADHD 치료용 아이패드 게임

king costs compared to both an active
ct control group, attaining levels beyond
d 20-year-old participants, with gains
hermore, age-related deficits in neural
ol, as measured with electroencephalo-
multitasking training (enhanced midline
al–posterior theta coherence). Critically,
mancebenefitsthatextendedtountrained
hanced sustained attention and working
midline frontal theta power predicting
n sustained attention and preservation
t 6 months later. These findings high-
he prefrontal cognitive control system
de the first evidence, to our knowledge,
deogamecanbeusedtoassesscognitive
valuate underlying neural mechanisms,
for cognitive enhancement.
aluated multitasking performance across
4 participants spanning six decades of life
er decade) played a diagnostic version of
rceptualdiscriminationability(‘signtask’)
isuomotortrackingtask(‘drivingtask’;see
or details of NeuroRacer). Performance
ct game conditions: ‘sign only’ (respond
earance of a sign only when a green circle
ve’ (simultaneously perform the sign task
centre of a winding road using a joystick
rceptual discrimination performance was
ionmetricofdiscriminability(d9).A‘cost’
titasking performance by calculating the
‘sign only’ to ‘sign and drive’, such that
gative percentage cost) indicates increased
sly engaging in the two tasks (see Methods
multitasking costs, an adaptive staircase
mine the difficulty levels of the game at
med the perceptual discrimination and
lifespan observed for fluid cognitive abilities, such as reasoning5
and
working memory6
. Thus, using NeuroRacer as a performance assess-
ment tool, we replicated previously evidenced age-related multitasking
deficits7,8
, and revealed that multitasking performance declines linearly
as we advance in age beyond our twenties.
In a second experiment, we explored whether older adults who trained
by playing NeuroRacer in multitasking mode would exhibit improve-
mentsintheirmultitaskingperformanceonthegame9,10
(thatis,diminished
NeuroRacer costs). Critically, we also assessed whether this training
alifornia, San Francisco, California 94158, USA. 2
Department of Physiology, University of California, San Francisco, California 94158, USA. 3
Center for Integrative
Francisco, California 94158, USA. 4
Department of Psychiatry, University of California, San Francisco, California 94158, USA.
1
month
MultitaskingSingle taskNo-contact
control
Initial
visit
NeuroRacer
EEG and
cognitive
testing
Drive only Sign only Sign and drive
and
1 hour × 3 times per week × 1 month
or
Single task Multitask
6+
months
Training intervention
NeuroRacer
or
a
b
+ +
Figure 1 | NeuroRacer experimental conditions and training design.
a, Screen shot captured during each experimental condition. b, Visualization of
training design and measures collected at each time point.
LETTER doi:10.1038/nature12486
Video game training enhances cognitive control in
older adults
J. A. Anguera1,2,3
, J. Boccanfuso1,3
, J. L. Rintoul1,3
, O. Al-Hashimi1,2,3
, F. Faraji1,3
, J. Janowich1,3
, E. Kong1,3
, Y. Larraburo1,3
,
C. Rolle1,3
, E. Johnston1
& A. Gazzaley1,2,3,4
Cognitivecontrolisdefinedbyasetofneuralprocessesthatallowusto
interact with our complex environment in a goal-directed manner1
.
Humans regularly challenge these control processes when attempting
to simultaneously accomplish multiple goals (multitasking), generat-
ing interference as the result of fundamental information processing
limitations2
. It is clear that multitasking behaviour has become ubi-
quitous in today’s technologically dense world3
, and substantial evid-
ence has accrued regarding multitasking difficulties and cognitive
control deficits in our ageing population4
. Here we show that multi-
tasking performance, as assessed with a custom-designed three-
dimensional video game (NeuroRacer), exhibits a linear age-related
decline from 20 to 79 years of age. By playing an adaptive version of
NeuroRacer in multitasking training mode, older adults (60 to 85
years old) reduced multitasking costs compared to both an active
control group and a no-contact control group, attaining levels beyond
those achieved by untrained 20-year-old participants, with gains
persisting for 6 months. Furthermore, age-related deficits in neural
signatures of cognitive control, as measured with electroencephalo-
graphy,wereremediated by multitasking training (enhanced midline
frontal theta power and frontal–posterior theta coherence). Critically,
thistrainingresultedinperformancebenefitsthatextendedtountrained
cognitive control abilities (enhanced sustained attention and working
memory), with an increase in midline frontal theta power predicting
the training-induced boost in sustained attention and preservation
of multitasking improvement 6 months later. These findings high-
light the robust plasticity of the prefrontal cognitive control system
inthe ageing brain, and provide the first evidence, to our knowledge,
ofhowacustom-designedvideogamecanbeusedtoassesscognitive
abilities across the lifespan, evaluate underlying neural mechanisms,
and serve as a powerful tool for cognitive enhancement.
In a first experiment, we evaluated multitasking performance across
the adult lifespan. A total of 174 participants spanning six decades of life
(ages 20–79; ,30 individuals per decade) played a diagnostic version of
NeuroRacertomeasuretheirperceptualdiscriminationability(‘signtask’)
withandwithoutaconcurrentvisuomotortrackingtask(‘drivingtask’;see
Supplementary Information for details of NeuroRacer). Performance
was evaluated using two distinct game conditions: ‘sign only’ (respond
as rapidly as possible to the appearance of a sign only when a green circle
was present); and ‘sign and drive’ (simultaneously perform the sign task
while maintaining a car in the centre of a winding road using a joystick
(that is, ‘drive’; see Fig. 1a)). Perceptual discrimination performance was
evaluatedusingthesignaldetectionmetricofdiscriminability(d9).A‘cost’
index was used to assess multitasking performance by calculating the
percentage change in d9 from ‘sign only’ to ‘sign and drive’, such that
greater cost (that is, a more negative percentage cost) indicates increased
interference when simultaneously engaging in the two tasks (see Methods
Summary).
Prior to the assessment of multitasking costs, an adaptive staircase
algorithm was used to determine the difficulty levels of the game at
which each participant performed the perceptual discrimination and
visuomotor tracking tasks in isolation at ,80% accuracy. These levels
were then used to set the parameters of the component tasks in the
multitasking condition, so that each individual played the game at a
customizedchallengelevel.Thisensuredthatcomparisonswouldinform
differences in the ability to multitask, and not merely reflect disparities in
component skills (see Methods, Supplementary Figs 1 and 2, and Sup-
plementary Information for more details).
Multitasking performance diminished significantly across the adult
lifespan in a linear fashion (that is, increasing cost, see Fig. 2a and Sup-
plementaryTable1),withtheonlysignificantdifferenceincostbetween
adjacent decades being the increase from the twenties (226.7% cost) to
the thirties (238.6% cost). This deterioration in multitasking perform-
ance is consistent with the pattern of performance decline across the
lifespan observed for fluid cognitive abilities, such as reasoning5
and
working memory6
. Thus, using NeuroRacer as a performance assess-
ment tool, we replicated previously evidenced age-related multitasking
deficits7,8
, and revealed that multitasking performance declines linearly
as we advance in age beyond our twenties.
In a second experiment, we explored whether older adults who trained
by playing NeuroRacer in multitasking mode would exhibit improve-
mentsintheirmultitaskingperformanceonthegame9,10
(thatis,diminished
NeuroRacer costs). Critically, we also assessed whether this training
1
Department of Neurology, University of California, San Francisco, California 94158, USA. 2
Department of Physiology, University of California, San Francisco, California 94158, USA. 3
Center for Integrative
Neuroscience, University of California, San Francisco, California 94158, USA. 4
Department of Psychiatry, University of California, San Francisco, California 94158, USA.
1
month
MultitaskingSingle taskNo-contact
control
Initial
visit
NeuroRacer
EEG and
cognitive
testing
Drive only Sign only Sign and drive
and
1 hour × 3 times per week × 1 month
or
Single task Multitask
6+
months
Training intervention
NeuroRacer
or
a
b
+ +
Figure 1 | NeuroRacer experimental conditions and training design.
a, Screen shot captured during each experimental condition. b, Visualization of
training design and measures collected at each time point.
5 S E P T E M B E R 2 0 1 3 | V O L 5 0 1 | N A T U R E | 9 7
멀티 태스킹: 운전 + 신호 포착

transferred to enhancements in their cognitive control abilities11
beyond
during game play as a key mechanistic feature of the tr
In addition, although cost reduction was observed o
group, equivalent improvement in component task sk
byboth STTandMTT(seeSupplementary Figs 4 and
that enhancedmultitaskingabilitywas notsolelythere
component skills, but a function of learning to reso
generated by the two tasks when performed concurr
the d9 cost improvement following training was not th
trade-off, as driving performance costs also diminish
group from pre- to post-training (see Supplementa
Notably in the MTT group, the multitasking per
remained stable 6 months after training without boo
6 months, 221.9% cost). Interestingly, the MTT grou
cost improved significantly beyond the cost level attain
20 year olds who played a single session of NeuroRac
experiment 3; P , 0.001).
Next, we assessed if training with NeuroRacer le
enhancementsofcognitivecontrolabilitiesthatareknow
in ageing (for example, sustained attention, divided at
memory; see Supplementary Table 2)12
. We hypothe
immersed in a challenging, adaptive, high-interferen
for a prolonged period of time (that is, MTT) would
cognitive performance on untrained tasks that also dem
control. Consistent with our hypothesis, significant
interactions and subsequent follow-up analyses eviden
training improvements in both working memory (del
task with and without distraction7
; Fig. 3a, b) and su
†
–100%
–90%
–80%
–70%
–60%
–50%
–40%
–30%
–20%
–10%
Multitaskingcost(d′)
†
*
ba
1
month
later
6
months
later
Experiment 1: lifespan Experiment 2: training
Single task training
No-contact control
Multitasking training
0%
20s 30s 40s 50s 60s 70s Initial
Figure 2 | NeuroRacer multitasking costs. a, Costs across the lifespan
(n 5 174) increased (that is, a more negative percentage) in a linear fashion
when participants were grouped by decade (F(1,5) 5 135.7, P , 0.00001) or
analysed individually (F(1,173) 5 42.8, r 5 0.45, P , 0.00001; see
Supplementary Fig. 3), with significant increases in cost observed for all age
groups versus the 20-year-old group (P , 0.05 for each decade comparison).
b, Costs before training, 1 month post-training, and 6 months post-training
showed a session X group interaction (F(4,72) 5 7.17, P , 0.0001, Cohen’s
d 5 1.10), with follow-up analyses supporting a differential benefit for the
MTT group (Cohen’s d for MTT vs STT 5 1.02; MTT vs NCC5 1.20).
{P , 0.05 within group improvement from pre to post, *P , 0.05 between
groups (n 5 46). Error bars represent s.e.m.
0
100
200
Pre–post WM task with
distractions (RT)
difference(ms)
†
*
a
0
100
200
Pre–po
without d
difference(ms)
†
b
RESEARCH LETTER
z
• 게임을 통한 고령층의 인지 능력 (멀티태스킹 능력) 개선 효과가 있음을 증명

• 60-85세 참가자 46명을 4주간 뉴로레이서를 통해서 훈련

• 그 결과 훈련 받지 않은 20대보다 더 잘 하게 되었으며,

• 연습을 하지 않고 6개월이 지나도, 능력은 그대로 남아 있었다.
Nature 501, 97–101 (2013)
게임을 통한 인지 능력 개선 효과

(vigilance; test of variables of attention (T
group (Fig. 3c; see Supplementary Table
several statistical trendssuggestive of impr
ance on other cognitive controltasks (dual
and changedetectiontask;see analysisofco
in Supplementary Table 2). Note that alth
and sustained attention improvements w
rapid responses to test probes, neither im
alternative version of the TOVA) nor accu
cant group differences, revealing that traini
of a speed/accuracy trade-off. Importantl
ments were specific to working memory a
cesses, and not theresult ofgeneralized incr
as no group X session interactions were fou
tasks (a stimulus detection task and the dig
see Supplementary Table 2). Finally, only
significant correlation between multitaski
withNeuroRacer)andimprovementsonan
task (delayed-recognition with distraction
(Fig. 3d).
These important ‘transfer of benefits’ sug
lying mechanism of cognitive control was c
MTT with NeuroRacer. To assess this furth
basis of training effects by quantifying even
tions (ERSP) and long-range phase cohere
of each sign presented during NeuroRacer
Wespecificallyassessedmidlinefrontalthe
EEG measure of cognitive control (for exam
tained attention15
and interference resolutio
prefrontal cortex. In addition, we analysed
between frontal and posterior brain region
measure also associated with cognitive co
memory14
and sustained attention15
). Se
b Long-range theta coherence
Older adult post-training
PLV
(% coherence)
1 5 10
*
)
Initial
Older adults Younger adults
†
Midline frontal theta
Power(dB)
Initial
*
a
Older adults Younger adults
Older adult post-training
Single task
training
Multitasking
training
No-contact
control
3.40
3.05
2.70
2.35
1.65
1.30
0.95
0.60
0.25
–0.10
–0.45
–0.80
–1.15
–1.50
2.00
Nature 501, 97–101 (2013)
•노년층 실험군에서 기술이 향상될수록  
 
인지 기능을 담당하는 전전두엽 피질(prefrontal cortex)의  
 
활성이 높아지는 것이 관찰되었다.
뇌의 활성도를 통해서도 관찰

www.thelancet.com/digital-health Published online February 24, 2020 https://doi.org/10.1016/S2589-7500(20)30017-0 1
Articles
Lancet Digital Health 2020
Published Online
February 24, 2020
https://doi.org/10.1016/
S2589-7500(20)30017-0
See Online/Comment
https://doi.org/10.1016/
S2589-7500(20)30058-3
Psychiatry and Behavioral
Sciences, Duke University
Medical Center, Durham, NC,
USA (Prof S H Kollins PhD,
Prof R S E Keefe PhD); Duke
Clinical Research Institute,
Durham, NC, USA
(Prof S H Kollins); Akili
Interactive Labs, Boston, MA,
USA (D J DeLoss PhD,
E Cañadas PhD, J Lutz PhD);
Department of Psychiatry,
Virginia Commonwealth
University, Richmond, VA, USA
(Prof R L Findling MD); VeraSci,
Durham, NC, USA
(Prof R S E Keefe); Department
of Pediatrics, University of
Cincinnati College of Medicine,
Cincinnati, OH, USA
(Prof J N Epstein PhD); Meridien
Research & Lake Erie College of
Osteopathic Medicine,
Bradenton, FL, USA
(A J Cutler MD); and Psychiatry
and Neuroscience and
Physiology, SUNY Upstate
Medical University,
Syracuse, NY, USA
(Prof S V Faraone PhD)
Correspondence to:
Dr Scott Kollins, Psychiatry and
Behavioral Sciences, Duke
University Medical Center,
Durham, NC 27710, USA
scott.kollins@duke.edu
A novel digital intervention for actively reducing severity of
paediatricADHD (STARS-ADHD): a randomised controlledtrial
Scott H Kollins, Denton J DeLoss, Elena Cañadas, Jacqueline Lutz, Robert L Findling, Richard S E Keefe, Jeffery N Epstein, Andrew J Cutler,
StephenV Faraone
Summary
Background Attention-deficit hyperactivity disorder (ADHD) is a common paediatric neurodevelopmental disorder with
substantial effect on families and society. Alternatives to traditional care, including novel digital therapeutics, have
shown promise to remediate cognitive deficits associated with this disorder and may address barriers to standard
therapies, such as pharmacological interventions and behavioural therapy. AKL-T01 is an investigational digital
therapeutic designed to target attention and cognitive control delivered through a video game-like interface via at-home
play for 25 min per day, 5 days per week for 4 weeks. This study aimed to assess whether AKL-T01 improved attentional
performance in paediatric patients with ADHD.
Methods The Software Treatment for Actively Reducing Severity of ADHD (STARS-ADHD) was a randomised, double-
blind, parallel-group, controlled trial of paediatric patients (aged 8–12 years, without disorder-related medications) with
confirmed ADHD and Test of Variables of Attention (TOVA) Attention Performance Index (API) scores of −1·8 and
below done by 20 research institutions in the USA. Patients were randomly assigned 1:1 to AKL-T01 or a digital control
intervention. The primary outcome was mean change in TOVA API from pre-intervention to post-intervention. Safety,
tolerability, and compliance were also assessed. Analyses were done in the intention-to-treat population. This trial is
registered with ClinicalTrials.gov, NCT02674633 and is completed.
Findings Between July 15, 2016, and Nov 30, 2017, 857 patients were evaluated and 348 were randomly assigned to
receive AKL-T01 or control. Among patients who received AKL-T01 (n=180 [52%]; mean [SD] age, 9·7 [1·3] years) or
control (n=168 [48%]; mean [SD] age, 9·6 [1·3] years), the non-parametric estimate of the population median change
from baseline TOVA API was 0·88 (95% CI 0·24–1·49; p=0·0060). The mean (SD) change from baseline on the
TOVA API was 0·93 (3·15) in the AKL-T01 group and 0·03 (3·16) in the control group. There were no serious adverse
events or discontinuations. Treatment-related adverse events were mild and included frustration (5 [3%] of 180)
and headache (3 [2%] of 180). Patient compliance was a mean of 83 (83%) of 100 expected sessions played
(SD, 29·2 sessions).
Interpretation Although future research is needed for this digital intervention, this study provides evidence that
AKL-T01 might be used to improve objectively measured inattention in paediatric patients with ADHD, while
presenting minimal adverse events.
Funding Sponsored by Akili Interactive Labs.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Introduction
Attention-deficit hyperactivity disorder (ADHD) is a
neurodevelopmental disorder of persistent impaired
attention, hyperactivity, and impulsivity that negatively
affects daily functioning and quality of life. ADHD is
one of the most commonly diagnosed paediatric mental
health disorders, with a prevalence estimated to be 5%
worldwide,1
and exerts a substantial burden on families
and society.2
Front-line intervention for ADHD includes pharmaco-
logical and non-pharmacological interventions, which
have shown short-term efficacy.3–5
Existing treatments
have side-effects that limit their acceptability,6
are only
effective when administered, and may not be as effective
for reducing daily impairments versus ADHD symptoms.7
Pharmacotherapy may not be suitable for some patients
due to caregiver preferences or concerns about abuse,
misuse, and diversion. Barriers to access also limit the
use of behavioural interventions, given a shortage of
properly trained paediatric mental health specialists8
and
variability in insurance coverage for such services.9,10
Indeed, studies in both the USA and the UK have found
that most children with paediatric mental health needs do
not have proper access to services.11,12
Digital therapeutics for ADHD may address these
limitations with improved access, minimal side-effects,
and low potential for abuse. Numerous studies and
meta-analyses on digital interventions targeting specific
cognitive functions have attempted to assess the
magnitude of efficacy for children and adolescents with
ADHD. In general, the quality of the studies is low, and
many do not include a control group.3
Reported effect
Lancet Digital Health 2020
and between measures. This
ClinicalTrials.gov, NCT02674633
Role of the funding source
The funder had a role in stud
confirming data and statistical
the study. All authors had full a
study and were involved in
writing of the report. The corres
responsibility for the decision t
Results
Of 857 children screened for eli
randomly assigned to receive A
(n=168) between July 15, 2016, a
and appendix p 3). Demograph
istics at baseline are shown in t
The mean number of sessio
in the AKL-T01 group was 8
(83% instructed use; SD=29·2
control group used their int
500 min (96% instructed use).
There was a significant differe
groups on the primary effi
p=0·0060); non-parametric est
median change (Hodges-Lehm
(95% CI 0·24–1·49). The mean (
on the TOVA API was 0·93 (3·
and 0·03 (3·16) in the control gr
no intervention-group difference
IRS, ADHD-RS, ADHD-RS-I
Parent Inhibit and Working Me
ADHD-Rating Scale—Inattentive 21·9 (3·5) 21·6 (3·7)
ADHD-Rating Scale—Hyperactivity 17·1 (6·0) 16·7 (5·4)
Clinical Global Impressions—Severity† 4·5 (0·7) 4·6 (0·6)
Data are n (%) or mean (SD). AKL-T01=an investigational digital therapeutic.
*n=179 for AKL-T01. †Assessed only at baseline.
Table 1: Baseline characteristics
Figure 2: Primary endpoint:TOVA API mean (SE) change pre-intervention to
post-intervention in the intention-to-treat population
*Adjusted p<0·050; prespecifiedWilcoxon rank-sum test.Triangle represents
median change, pre-intervention to post-intervention.
AKL-T01 (n=169) Active control (n=160)
–0·25
0
0·25
0·50
0·75
1·00
1·25
1·50
Improvement
Mean(SE)changeinTOVAAPI
*
AKL-T01 Control χ² test p
•아동 ADHD 환자들에 대해서 EVO 게임을 하게 한 결과 (25분, 주 5회, 4주)

•TOVA API 에 대해서 대조군 대비 유의미한 개선 효과를 보임

PTSD (외상 후 스트레스 장애)

Prolonged Exposure Therapy
(지속 노출 치료)

환자에게 실감나는 전쟁 상황을

어떻게 시각화 해줄 것인가

버추얼 베트남
https://www.youtube.com/watch?v=c7MmgA_JG4g

•VR은 PTSD의 치료를 위해 1990년대부터 활용

•최초의 시도: 버추얼 베트남 (1997)

•정글 시나리오 / 군용 헬리곱터가 날아가는 시나리오

•그래픽 수준, 구현 효과 및 시나리오 등이 제한적

•전통적 심리 치료에 효과 없던 환자 전원이 유의미한 개선 효과
“영상 속에서 베트남 사람들과 탱크를 보았어요”
버추얼 베트남

https://www.youtube.com/watch?v=iMeEuSdJ7EU

(9.5) to 11.9 (13.6), (t=3.37, df=19, p < .003) and mean PHQ-9
decreased 49% from 13.3 (5.4) to 7.1 (6.7), (t=3.68, df=19, p < 0.00
Figure 4. PTSD Checklist scores across treatment Figure 5. BAI and PH
The average number of sessions for this sample was just under 1
successful treatment completers had documented mild and moder
injuries, which suggest that this form of exposure can be usefully
population. In spite of these initial positive results for treatment com
existed with dropouts from this active duty sample. Seven part
•연구 결과 20명의 환자들은 전반적으로 유의미한 개선을 보임

•환자들 전체의 PCL-M 수치가 평균 54.4에서 35.6으로 감소

•20명 중 16명은 치료 직후 더 이상 PTSD를 가지지 않은 것으로 나타남

•치료가 끝난지 3개월 후에 환자들의 상태는 유지
http://www.ncbi.nlm.nih.gov/pubmed/19377167

• Woebot, 정신 상담 챗봇

• 실제 상담사들이 하듯이, 대화형으로 설명하고 사용자의 정신 건강 상태를 체크

• 대부분 설문과 다를 것이 없지만 (정해진 답 중에 하나 선택), UI 상의 혁신이라고 볼 수 있음

• 아직까지는 아주 정교한 NLP를 사용하고 있지는 않음 (세션 당 한 번 정도)

depression at baseline as measured by the PHQ-9, while
three-quarters (74%, 52/70) were in the severe range for anxiety
as measured by the GAD-7.
Figure 1. Participant recruitment flow.
Table 1. Demographic and clinical variables of participants at baseline.
WoebotInformation control
Scale, mean (SD)
14.30 (6.65)13.25 (5.17)Depression (PHQ-9)
18.05 (5.89)19.02 (4.27)Anxiety (GAD-7)
25.54 (9.58)26.19 (8.37)Positive affect
24.87 (8.13)28.74 (8.92)Negative affect
22.58 (2.38)21.83 (2.24)Age, mean (SD)
Gender, n (%)
7 (21)4 (7)Male
27 (79)20 (55)Female
Ethnicity, n (%)
2 (6)2 (8)Latino/Hispanic
32 (94)22 (92)Non-Latino/Hispanic
28 (82)18 (75)Caucasian
6 (18)6 (25)Non-Caucasian
Fitzpatrick et alJMIR MENTAL HEALTH
Delivering Cognitive Behavior Therapy toYoung Adults With
Symptoms of Depression and Anxiety Using a Fully Automated
Conversational Agent (Woebot):A Randomized Controlled Trial
•분노장애와 우울증이 있다고 스스로 생각하는 대학생들이 사용

•목적: 챗봇의 feasibility, acceptability, preliminary efficacy 를 보기 위함

•대학생 총 70명을 대상으로 2주 동안 진행

•실험군 (Woebot): 34명

•대조군 (information-only): 31명

•기준: PHQ-9, GAD-7

Table 2. Results of ITT analysis of entire sample on primary outcomes in the study at T2.
d cPFWoebotInformation-only control
95% CIb
T2a
95% CIb
T2a
0.44.0176.039.74-12.3211.14 (0.71)12.07-15.2713.67 (.81)PHQ-9
0.14.5810.3816.16-18.1317.35 (0.60)15.52-18.5616.84 (.67)GAD-7
0.02.7070.1724.35-29.4126.88 (1.29)23.17-28.8626.02 (1.45)PANAS positive
affect
0.344.9120.9123.54-28.4225.98 (1.24)24.73-30.3227.53 (1.42)PANAS nega-
tive affect
a
Baseline=pooled mean (standard error)
b
95% confidence interval.
c
Cohen d shown for between-subjects effects using means and standard errors at Time 2.
Figure 2. Change in mean depression (PHQ-9) score by group over the study period. Error bars represent standard error.
Preliminary Efficacy
Table 2 shows the results of the primary ITT analyses conducted
on the entire sample. Univariate ANCOVA revealed a significant
treatment effect on depression revealing that those in the Woebot
group significantly reduced PHQ-9 score while those in the
information control group did not (F1,48=6.03; P=.017) (see
Figure 2). This represented a moderate between-groups effect
size (d=0.44). This effect is robust after Bonferroni correction
for multiple comparisons (P=.04). No other significant
between-group differences were observed on anxiety or affect.
Completer Analysis
As a secondary analysis, to explore whether any main effects
existed, 2x2 repeated measures ANOVAs were conducted on
the primary outcome variables (with the exception of PHQ-9)
among completers only. A significant main effect was observed
on GAD-7 (F1,54=9.24; P=.004) suggesting that completers
experienced a significant reduction in symptoms of anxiety
between baseline and T2, regardless of the group to which they
were assigned with a within-subjects effect size of d=0.37. No
main effects were observed for positive (F1,50=.001; P=.951;
d=0.21) or negative affect (F1,50=.06; P=.80; d=0.003) as
measured by the PANAS.
To further elucidate the source and magnitude of change in
depression, repeated measures dependent t tests were conducted
and Cohen d effect sizes were calculated on individual items of
the PHQ-9 among those in the Woebot condition. The analysis
revealed that baseline-T2 changes were observed on the
following items in order of decreasing magnitude: motoric
symptoms (d=2.09), appetite (d=0.65), little interest or pleasure
in things (d=0.44), feeling bad about self (d=0.40), and
concentration (d=0.39), and suicidal thoughts (d=0.30), feeling
down (d=0.14), sleep (d=0.12), and energy (d=0.06).
JMIR Ment Health 2017 | vol. 4 | iss. 2 | e19 | p.6http://mental.jmir.org/2017/2/e19/
Fitzpatrick et alJMIR MENTAL HEALTH
우울한 정도가 (PHQ-9)

대조군 대비 유의미한 감소

•Woebot 그룹에서는 우울증(PHQ-9)의 유의미한 감소

•대조군에서는 유의미한 감소 없음

대표적인 Digital Therapeutics의 사례연구
• Dthera Science
• Big Health
• AppliedVR
• Woebot
• Cognoa
• Neofect

Digital Therapeutics and Digital Medicine Summit | February 2018
After the endpoint:
how digital medicine can transcend
traditional research standards
Peter Hames, CEO & Co-Founder

Our first product
is Sleepio
• A fully automated Cognitive Behavioral
Therapy (CBT) program for insomnia
• Accessible via app and web, it is an
effective digital medicine for insomnia
• Helps alleviate co-morbid anxiety and
depression
For more info see bighealth.com/our-solution
•불면증에 대한 인지행동치료 (Cognitive Behavioral Therapy, CBT)

•인지 치료: 잠에 대한 잘못된 생각을 바로 잡는 치료 (교육, 자극 조절, 인지 재구성…)

•행동 치료: 잠에 방해가 되는 행동/습관 교정 (수면 위생법, 이완/호흡 훈련 …)

•불면증 개선 효과에 대한 임상적인 근거가 상당히 탄탄함

•30 개의 논문 (그 중 8 개는 무작위 대조군 임상 시험)

nature
“About as effective as CBT delivered in person”
THE LANCET
“A proven intervention for sleep disorders”
Reference: Espie et al. (2012), SLEEP. Average change in CBT group: SOL: 47 à 21mins, WASO: 76 à 28mins); Lancee et al. (2016), SLEEP.
% insomnia sufferers
achieving healthy sleep
Placebo Treatment as
usual
In-person
CBT-I
76%
29%
18%
70-75%
Validation of Sleepio’s effectiveness in
improving sleep quality

•영국의 NHS가 천만 명 규모의 영국인에게 Sleepio를 지불하기로 결정

•DTx의 무한한 확장성: 대규모 인원에게 단번에 약효를 전달할 수 있음

•미국의 대형 PBM(Pharmacy Benefit Manager)인 CVS Health

•Sleepio 의 보험 적용을 권장하기로 결정

•CVS Health는 미국인의 30% 정도의 처방약 결정에 관여

디지털 치료제, 누구도 가보지 않은 길

임상-인허가-보험-의사 처방-RWE-환자 사용(Real World Evidence)

임상-인허가-보험-의사 처방-RWE-환자 사용
• DTx에도 RCT가 필요한가
• 임상 연구 디자인은 어떻게 해야 하나
• 효용/가치를 어떻게 증명할 것인가
(Real World Evidence)

• 인허가 없이 공산품으로 판매할 것인지, 
의료기기 인허가를 받을 것인지 결정
• 인허가를 받겠다면, 어떤 규제 방식을 택할 것인가
• 규제기관은 DTx의 효능/부작용을 어떻게 심사할까

• 보험사는 DTx를 어떻게 바라볼까
• 수가를 받을 수 있는가/받아야 하는가

• 기존 약 대신에 의사가 처방할까
• 기존 약 대비 어떤 강점을 가져야 하나

• 의사들이 활용할 여건이 되는가
• EMR 속으로 어떻게 통합
• 진단/치료/관리 기준으로 활용 가능한가

• 의사들이 활용할 여건이 되는가
• EMR 속으로 어떻게 통합
• 진단/치료/관리 기준으로 활용 가능한가
• DTx를 처방 받으면 환자는 어떻게 느낄까
• 지속사용성: 지속해서 사용할까
• 디지털 리터러시: 사용성에 지장은 없는가

Feedback/Questions
• E-mail: yoonsup.choi@gmail.com
• Blog: http://www.yoonsupchoi.com
• Facebook: 최윤섭 디지털 헬스케어 연구소

Digital Therapeutics,
약인가 의료기기인가?
•치료 효과를 가진 '소프트웨어’ 의료기기
•SaMD: 디지털 혁신 때문에 의료 기기의 범주가 확장
•FDA에서도 CDRH (의료기기 심사부)에서 인허가

디지털 헬스케어
의료기기
최윤섭 디지털 헬스케어 연구소

소장 최윤섭, PhD

yoonsup.choi@gmail.com

*SaMD: Software as a Medical Device
의료기기


S/W
SaMD*

의료기기
런키퍼

슬립싸이클
엑스레이 기기

혈압계

체온계
엠페티카

얼라이브코어

프로테우스
(활동량 측정 웨어러블)
(달리기 모니터링 앱)
(수면 모니터링 앱)
(뇌전증 발작 측정 웨어러블)
(심전도 측정 가젯)
(복약 측정용 먹는 센서)
하드웨어 기반의

의료기기들


S/W
SaMD*
핏빗

의료기기
런키퍼

슬립싸이클
엑스레이 기기

혈압계

체온계
엠페티카

얼라이브코어

프로테우스
의료 인공지능
왓슨
(암 환자

진료 보조)

의료기기들


S/W
SaMD*
뷰노 루닛
지브라 메디컬 IDx
(엑스레이 기흉 등) (안저 사진 당뇨성 망막병증)
(엑스레이 골연령 등) (엑스레이 폐결절 등)
핏빗

의료기기
디지털 치료제
런키퍼

슬립싸이클
엑스레이 기기

혈압계

체온계
엠페티카

얼라이브코어

프로테우스
의료 인공지능
왓슨
캄
페어
알킬리
어플라이드VR
(암 환자

진료 보조)
(명상 앱)
(중독 치료앱)
(ADHD 치료용 게임)
(진통 효과 VR)

의료기기들


S/W
SaMD*
뷰노 루닛
지브라 메디컬 IDx
(엑스레이 기흉 등) (안저 사진 당뇨성 망막병증)
(엑스레이 골연령 등) (엑스레이 폐결절 등)
핏빗

제품의 목적 1. 건강 관리 2. 질병의 관리/예방
3. 다른 의약품의

최적화
4. 질병 치료
제품의 유효성,

위해도, 사용 목적

등에 대한 주장
규제 기관 재량

(항상 규제 받는 것은 아님)
제3자의 검증이 필요하며, 규제 기관의 규제를 받음
질병과 관련된

제품의 주장 범위
질병에 관련한 유효성

주장은 허용되지 않음
낮음~중간의 위해도

(eg. 질병의 진행 속도를

늦춰줌)
중간~높은 위해도

(eg. 기존 약제의

유효성을 높여줌)
중간~높은 위해도

(eg. 질병 치료 등

의학적인 유효성)
임상적인 근거 임상 시험이 필요하며, 지속적인 근거의 창출이 필요
구매 방식
환자 직접 구매 (DTC) 
(의사 처방 필요 x)
일반의약품 (over-the-counter) 
혹은 의사 처방 필요
의사 처방 필요
다른 약제와의 관계
독립적으로 사용  
or 다른 약제 간접 지원
단독 투여 
or 
병용 투여
병용 투여
단독 투여 
or 
병용 투여
디지털 치료제의 종류
Digital Therapeutics Alliance (DTA) white paper, 2018

• 노바티스는 시리즈A (2016.2)이어, 시리즈B (2018.1) 펀딩에도 참여
• 테마섹에서 리드 (테마섹은 Akili 시리즈B도 리드)

•Akili Interactive

•2016년 7월, $42.4m 규모의 Series B 펀딩 (암젠, 머크 등이 참여)

•2018년 5월, $55m 규모의 Series C 펀딩 (암젠, 머크 등이 참여)

•2018년 연내로 FDA 승인을 받는 것이 목표였으나, 2019년에 결정될 것으로 예상

•2018년 11월 기준, FDA 리뷰 중

• 사노피 벤처스에서 $17M 규모의 Venture Round 를 리드 (2018.7)
• depression, insomnia, acute coronary syndrome, and chronic pain.

Recent DTx Regulatory Milestones
3
Pear receives FDA
de novo clearance
for reSET
September 2017
FDA launches Digital
Health pre-cert pilot
program;
Includes Pear
September 2017
Pear granted FDA
Breakthrough
designation for
reSET-O
October 2017
Dthera granted
Breakthrough
designation from FDA
August 2018
Pear receives FDA
510(k) clearance
for reSET-O
December 2018
NightWare granted
Breakthrough
designation from
FDA
May 2019
Cognoa granted
Breakthrough
designation from
FDA
February 2019
Palo Alto Health
receives FDA
clearance for
Freespira
August 2018
•미국에서는 DTx 와 관련된 인허가/규제 관련 마일스톤이 계속 만들어지고 있음

•특히 Breakthrough Designation 을 통한 regulatory pathway를 많이 이용

•Dthera, Cognoa, Nightware

•현재 FDA 인허가 받은 DTx는 7~8개 정도로 추산

•인허가와 의료 관련 claim 없이 판매하는 전략을 택한 곳도 있음

DTxDM West 
(2018.10 at SiliconValley)

•국내에서는 시작도 전에 이미 hype이 존재.

•최근 몇개월 사이 갑자기 ‘디지털 치료제’ 키워드가 언론에 등장

•초기 스타트업 중에서도 이 키워드를 쓰는 곳 증가 / 대기업들도 관심을 가지기 시작

•관계 부처들 사이에서도 이니셔티브 경쟁 시작

•정의, 범주 등에서 제각각 + 유행에 편승하려는 업체들

•내년이 아마 국내에서는 원년… 정도가 될 것으로 예상.

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