(228 days)
Yes
The device description explicitly mentions "adaptive algorithms (also known as Selective Stimulus Management Engine, SSME™)" and describes a "closed-loop system" where these algorithms "automatically adjust the difficulty level for a personalized treatment experience." This adaptive and personalized adjustment based on user performance is characteristic of machine learning or AI techniques.
Yes
The device description and intended use clearly state that EndeavorOTC is a "digital therapeutic" indicated to "improve attention" and should be used as "part of a therapeutic program."
No
The "Intended Use / Indications for Use" section states, "EndeavorOTC is a digital therapeutic indicated to improve attention... EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program..." This indicates it is a treatment device, not a diagnostic one. While it assesses attention, it does so to monitor improvement from its therapeutic intervention, not to diagnose a condition.
Yes
The device description explicitly states "EndeavorOTC is software-as-a-medical device (SaMD)". It also describes the device residing on a user's mobile device and utilizing the mobile device's internal components (accelerometer, touch screen, display, speaker) for input and output, without mentioning any additional hardware components provided as part of the medical device itself.
Based on the provided information, EndeavorOTC is not an In Vitro Diagnostic (IVD).
Here's why:
- IVDs analyze biological samples: IVDs are designed to examine specimens taken from the human body (like blood, urine, tissue) to provide information about a person's health.
- EndeavorOTC is a digital therapeutic: EndeavorOTC is a software-based treatment that interacts directly with the user through a game-like interface on a mobile device. It aims to improve attention through engaging cognitive tasks, not by analyzing biological samples.
- The intended use and device description clearly state its purpose: The documentation describes EndeavorOTC as a digital therapeutic for improving attention in individuals with ADHD, measured by computer-based testing (TOVA®). This is a behavioral and cognitive intervention, not a diagnostic test based on biological analysis.
Therefore, EndeavorOTC falls under the category of a digital therapeutic or software-as-a-medical device (SaMD), not an In Vitro Diagnostic.
No
The letter does not explicitly state that the FDA has reviewed, approved, or cleared a PCCP for this specific device.
Intended Use / Indications for Use
EndeavorOTC is a digital therapeutic indicated to improve attention as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medicational programs, which further address symptoms of the disorder.
Product codes
QFT
Device Description
EndeavorOTC is software-as-a-medical device (SaMD) that resides on the user's mobile device and can be executed at home.
It is an over-the-counter (OTC) digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder.
The device is built on Akili's proprietary, patented, technology platform. EndeavorOTC uses adaptive algorithms (also known as Selective Stimulus Management Engine, SSME™) to deliver stimuli that are designed to engage the patient in a manner that improves their attention function. In a closed-loop system, the adaptive SSME™ algorithms automatically adjust the difficulty level for a personalized treatment experience that is tailored to the needs of each individual patient.
EndeavorOTC is delivered through a video game experience which leverages art, music, storytelling, and reward cycles to keep patients engaged. The adaptive algorithm constantly pushes patients precisely at predefined performance bounds relative to each individual, such that they are continuously encouraged to exceed their historic performance. The science behind EndeavorOTC was developed at the University of California, San Francisco by Adam Gazzaley, M.D., Ph.D., Founding Director of the University of California San Francisco's Neuroscape and Akili's Chief Science Advisor.
The basic program inputs are steering, which is accomplished by using the mobile device's internal accelerometer to measure the degree to which it is tilted, and tapping, which is accomplished using the touch screen to measure correct and incorrect targeting. The basic outputs are the visual display of the game progression along with audio, which is accomplished by using the internal high resolution display and internal speaker. The program includes features to ensure it is used per the recommended regimen (approximately 25 minutes per day, 5 days per week, for 6 weeks).
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
18 and older
Intended User / Care Setting
Over-the-counter use. Patient facing software executed at home.
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Clinical performance testing was conducted to evaluate the efficacy and safety of EndeavorOTC in adults 18 years of age and older. Efficacy was determined primarily by the change from baseline in a digitally assessed measure of sustained and selective attention, the Test of Variables of Attention (TOVA®), after 6 weeks of treatment. The multicenter open-label study enrolled 221 subjects with inattentive or combined-type ADHD. A diagnosis of ADHD was determined in study participants using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria as confirmed by the Mini-International Neuropsychiatric Interview (MINI) for ADHD adult version 7.0.2. All 221 participants who were enrolled in the adult study were included in the Safety population (also known as ITT or intent to treat population, is all subjects enrolled in the study), and 153 participants were included in the Efficacy Population (also known as the mITT or modified intent to treat population, is all enrolled subjects with drop outs excluded). Safety population is all participants who were exposed to AKL-T01 intervention. Efficacy population is all participants who took the AKL-T01 intervention home and completed both baseline and day 42 exit visit assessments (including TOVA).
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Study Type: Single arm, open-label, adaptive design clinical performance study.
Sample Size: 221 subjects enrolled in the Safety (ITT) population, 153 subjects in the Efficacy (mITT) population.
Key Results:
- Primary Endpoint (TOVA-ACS Score): Analysis of the primary efficacy endpoint in the Efficacy Population (N=153) showed a statistically significant positive mean change from baseline to study day 42 in the TOVA of 6.460 (SD 6.9522 [95% Cl: 5.349, 7.570]; P
§ 882.5803 Digital therapy device for Attention Deficit Hyperactivity Disorder.
(a)
Identification. A digital therapy device for Attention Deficit Hyperactivity Disorder (ADHD) is a software intended to provide therapy for ADHD or any of its individual symptoms as an adjunct to clinician supervised treatment.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Clinical performance testing must demonstrate and document the following under the labeled conditions for use, which include considerations for the ability of the device to:
(i) Use a validated measure to evaluate effectiveness of device to provide therapy for ADHD or any of its individual symptoms; and
(ii) Capture all adverse events.
(2) Software must be described and provided in a clear and detailed manner to include all features and functions of the software implementing the digital therapy. Software verification, validation, and hazard analysis must also be provided.
(3) The labeling must include the following items:
(i) Patient and physician labeling must include instructions for use, including images that demonstrate how to interact with the device;
(ii) Patient and physician labeling must list the minimum operating system (OS) requirements that support the software of the device;
(iii) Patient and physician labeling must include a warning that the digital therapy device is not intended for use as a standalone therapeutic device;
(iv) Patient and physician labeling must include a warning that the digital therapy device does not represent a substitution for the patient's medication; and
(v) Physician labeling must include a summary of the clinical performance testing conducted with the device.
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June 14, 2024
Akili Interactive Labs, Inc. % Bhupinder Singh Head of Quality and Regulatory Affairs 22 Boston Wharf Rd 7th Floor Boston, MA 02110
Re: K233496
Trade/Device Name: EndeavorOTC Regulation Number: 21 CFR 882.5803 Regulation Name: Digital therapy device for attention deficit hyperactivity disorder Regulatory Class: Class II Product Code: QFT Dated: May 16, 2024 Received: May 16, 2024
Dear Bhupinder Singh:
We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"
1
(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
2
Sincerely,
Robert Kang -S
for Pamela Scott, MS Assistant Director DHT5B: Division of Neuromodulation and Physical Medicine Devices OHT5: Office of Neurological and Physical Medicine Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
3
Indications for Use
510(k) Number (if known) K233496
Device Name EndeavorOTC
Indications for Use (Describe)
EndeavorOTC is a digital therapeutic indicated to improve attention as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medicational programs, which further address symptoms of the disorder.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ------------------------------------------------- | -- |
Prescription Use (Part 21 CFR 801 Subpart D)
X Over-The-Counter Use (21 CFR 801 Subpart C)
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7. 510(k) Summary
This 510(k) summary of safety and effectiveness information is prepared in accordance with 21 CFR § 807.92.
| Date Prepared: | October 30, 2023 |
|---|---|
| Legal Manufacturer: | Akili Interactive Labs, Inc. |
| 71 Commercial St | |
| Mailbox 312 | |
| Boston, MA 02109 | |
| Primary Contact Person: | Bhupinder Singh |
| Head of Quality and Regulatory Affairs | |
| Phone: +1 (408) 832-7124 | |
| E-mail: bsingh@akiliinteractive.com |
Regulatory Information
| Device Trade Name: | EndeavorOTC |
|---|---|
| Device Classification Name: | Digital Therapeutic Software for Attention Deficit |
| Hyperactivity Disorder | |
| Regulation Number: | 21 CFR § 882.5803 |
| Classification Product Code: | QFT |
| Review Advisory Committee: | Neurology |
| Device Classification: | Class II |
| 510(k) Number | K233496 |
| Predicate Device Information | |
| Device Manufacturer: | Akili Interactive Labs, Inc. |
| Submission Number: | DEN200026 |
| Device Name: | EndeavorRx |
| Other Reference Device | EndeavorRx (K231337) |
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Image /page/5/Picture/0 description: The image shows the word ".KILI" in a stylized, sans-serif font. The letters are white against a blue background. The letters are rounded and have a modern look.
Device Description:
EndeavorOTC is software-as-a-medical device (SaMD) that resides on the user's mobile device and can be executed at home.
It is an over-the-counter (OTC) digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder.
The device is built on Akili's proprietary, patented, technology platform. EndeavorOTC uses adaptive algorithms (also known as Selective Stimulus Management Engine, SSME™) to deliver stimuli that are designed to engage the patient in a manner that improves their attention function. In a closed-loop system, the adaptive SSME™ algorithms automatically adjust the difficulty level for a personalized treatment experience that is tailored to the needs of each individual patient.
EndeavorOTC is delivered through a video game experience which leverages art, music, storytelling, and reward cycles to keep patients engaged. The adaptive algorithm constantly pushes patients precisely at predefined performance bounds relative to each individual, such that they are continuously encouraged to exceed their historic performance. The science behind EndeavorOTC was developed at the University of California, San Francisco by Adam Gazzaley, M.D., Ph.D., Founding Director of the University of California San Francisco's Neuroscape and Akili's Chief Science Advisor.
The basic program inputs are steering, which is accomplished by using the mobile device's internal accelerometer to measure the degree to which it is tilted, and tapping, which is accomplished using the touch screen to measure correct and incorrect targeting. The basic outputs are the visual display of the game progression along with audio, which is accomplished by using the internal high resolution display and internal speaker. The program includes features to ensure it is used per the recommended regimen (approximately 25 minutes per day, 5 days per week, for 6 weeks).
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Image /page/6/Picture/0 description: The image features the word ".AKILI" in a stylized, sans-serif font. The letters are white against a blue background. The font is rounded and has a playful, modern look.
Indications for Use: EndeavorOTC is a digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC demonstrate improvements in a digitally assessed measure, Test of Variables of Attention (TOVA®) of sustained and selective attention and may not display benefits in typical behavioral symptoms such as hyperactivity. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder. Limitations EndeavorOTC may not be appropriate for users with photo-sensitive
epilepsy, color blindness, or physical limitations that restrict use of a mobile device. It is recommended that users speak to their health care provider before starting EndeavorOTC treatment. EndeavorOTC is not for persons who have a comorbid psychiatric condition in addition to ADHD. When using this device it is recommended that users seek care from a medical health care provider in conjunction with its use.
NOTE: This single arm study did not include a sham control group and it is therefore possible that observed effects were due to bias or placebo effects. Akili has conducted and published additional studies that support the lack of a placebo effect on the TOVA2-2. Patients and health care providers should consider the totality of the clinical evidence in light of this before using this product.
² Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
2 Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
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Summary of Technological Characteristics
| Attribute | Subject Device:
EndeavorOTC | Predicate Device:
EndeavorRx (DEN200026) | Comparison |
|-------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Manufacturer | Akili Interactive Labs, Inc. | Akili Interactive Labs, Inc. | Same |
| Device
Classification
Name | Digital Therapeutic
Software for Attention
Deficit Hyperactivity
Disorder | Digital Therapeutic Software for
Attention Deficit Hyperactivity
Disorder | Same |
| Product Code | QFT | QFT | Same |
| Regulation
Number | 21 CFR § 882.5803 | 21 CFR § 882.5803 | Same |
| Intended use | Digital therapeutic adaptive
stimulus software for the
closed-loop treatment of
psychiatric disorders and
cognitive dysfunction
associated with medical
conditions. | Digital therapeutic adaptive
stimulus software for the closed-
loop treatment of psychiatric
disorders and cognitive
dysfunction associated with
medical conditions. | Same |
| Indication of
Use | EndeavorOTC is an over the
counter digital therapeutic
indicated to improve
attention function as
measured by computer-
based testing in patients 18
and older with primarily
inattentive or combined
type ADHD, who have a
demonstrated attention
issue. Patients who engage
with EndeavorOTC
demonstrate improvements
in a digitally assessed
measure, Test of Variables
of Attention (TOVA®) of
sustained and selective
attention and may not
display benefits in typical
behavioral symptoms such
as hyperactivity. | EndeavorRx is a digital
therapeutic indicated to
improve attention function as
measured by computer based
testing in children ages 8-12
years old with primarily
inattentive or combined-type
ADHD, who have a
demonstrated attention issue.
Patients who engage with
EndeavorRx demonstrate
improvements in a digitally
assessed measure Tests of
Variables of Attention (TOVA) of
sustained and selective
attention and may not display
benefits in typical behavioral
symptoms, such as
hyperactivity. EndeavorRx
should be considered for use as
part of a therapeutic program | Substantially
equivalent.
EndeavorOTC is
indicated for 18
years of age or
older, compared
to the predicate
device (8-12
years). The
difference in age
range do not
change the
intended use of
the device, and
clinical testing
demonstrates
the subject
device is safe
and effective in
the adult
population. |
| | EndeavorOTC is not
intended to be a
replacement for any form of
treatment and should be
used as part of a
therapeutic program that
may include clinician-
directed therapy,
medication, and/or
educational programs,
which further address
symptoms of the disorder | that may include: clinician-
directed therapy, medication,
and/or educational programs,
which further address symptoms
of the disorder. | Product
indication was
changed from Rx
to OTC. See
Access row
below for
further
discussion. |
| System
Components | Patient facing video game
application | Patient facing video game
application | Same |
| | Mobile device platform | Mobile device platform | |
| Proprietary
Algorithm | Selective Stimulus
Management Engine
(SSMETM) | Selective Stimulus Management
Engine (SSMETM) | Same |
| Basic
Operations | Steering, Tapping, Multi-
tasking | Steering, Tapping, Multi-tasking | Same |
| Presentation | Structured manner across
game "Challenges" and
"Worlds" | Structured manner across game
"Challenges" and "Worlds" | Same |
| Mobile
Platform
Compatibility | iOS and Android | iOS and Android | Same |
| Access | Over-the-counter use. It is
recommended that patients
speak to their health care
provider before starting
EndeavorOTC treatment.
See section, "Summary of
Clinical Performance Data"
below for supporting data. | Prescription use only.
Authorized and overseen by a
licensed health care provider. | Labeling
modifications
were made to
support over-
the-counter use,
and human
factors
validation
testing confirms
the change to
OTC does not
raise different
questions. |
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Summary of Non-Clinical Performance Data: Bench software testing has been performed on the EndeavorOTC and demonstrates compliance with the following international and FDArecognized consensus standards and FDA guidance documents:
- ISO 14971:2019 Medical devices - Application of risk management to medical devices
- IEC 62304 Edition 1.1 2015-06 CONSOLIDATED VERSION Medical device software - Software life cycle processes
- IEC 82304-1 Edition 1.0 2016-10 Health software - Part 1: General requirements for product safety
- FDA Guidance Document for Industry and FDA Staff -Content of Premarket Submissions for Device Software Functions - Guidance for Industry and Food and Druq Administration Staff (Final Guidance issued June 14, 2023)
- . FDA Guidance Document for Industry and FDA Staff -Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions: Guidance for Industry and Food and Drug Administration Staff (Final Guidance issued September 27, 2023)
The results of bench software verification and validation testing supports that EndeavorOTC functions as intended.
Human factors validation testing was performed to ensure that EndeavorOTC is safe and effective for intended users, use, and use environments, and demonstrates compliance with the following additional standards and guidance document:
- ANSI/AAMI/IEC 62366-1:2015/ Amd 1: 2020 Medical Devices -Part 1: Application of Usability Engineering to Medical Devices - Amendment 1
- ANSI/AAMI/IEC 62366-2:2016 Medical Devices Part 2: ● Guidance on the application of usability engineering to medical devices
- FDA Guidance Document for Industry for Industry and FDA Staff - Applying Human Factors and Usability Engineering to Medical Devices, issued February 3, 2016
The results of the human factors validation testing supports the usability of EndeavorOTC in intended users, for the intended use, in the intended use environment.
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Summary of Clinical Data: Clinical performance testing was conducted to evaluate the efficacy and safety of EndeavorOTC in adults 18 years of age and older. 3 Efficacy was determined primarily by the change from baseline in a digitally assessed measure of sustained and selective attention, the Test of Variables of Attention (TOVA®), after 6 weeks of treatment. The multicenter open-label study enrolled 221 subjects with inattentive or combined-type ADHD. A diagnosis of ADHD was determined in study participants using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria as confirmed by the Mini-International Neuropsychiatric Interview (MINI) for ADHD adult version 7.0.2. All 221 participants who were enrolled in the adult study were included in the Safety population (also known as ITT or intent to treat population, is all subjects enrolled in the study), and 153 participants were included in the Efficacy Population (also known as the mlTT or modified intent to treat population, is all enrolled subjects with drop outs excluded). Safety population is all participants who were exposed to AKL-T01 intervention. Efficacy population is all participants who took the AKL-T01 intervention home and completed both baseline and day 42 exit visit assessments (including TOVA).
Seventy-five participants (33.9%) discontinued the study: the most common reason for study discontinuation was withdrawal by participant. Reasons for withdrawal by participants include the following: experiencing technical bugs or technical issues; game took too much time away from school, work, or other activities; did not like AKL-T01; did not want to complete the on-site study activities any further. Three (1.7%) participants discontinued the study due to adverse events (1 headache, 2 nausea).
For further description of the adult study in comparison to the predicate studies, see Table 1 - comparison of clinical study design description.
The results of the clinical performance study support the performance and safety of EndeavorOTC in the adult age range. Analysis of the primary efficacy endpoint in the Efficacy Population (N=153) showed a statistically significant positive mean change from baseline to study day 42 in the TOVA of 6.460 (SD 6.9522 [95% Cl: 5.349, 7.570]; P 3 Stamatis, C. A., Mercaldi, C., & Kollins, S. H. (2023). A Single-Arm Pivotal Trial to Assess the Efficacy of Akl-T01, a Novel Digital Intervention for Attention, in Adults Diagnosed With ADHD. Journal of the American Academy of Child & Adolescent Psychiatry, 62(10), S318
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secondary efficacy endpoints in the Efficacy Population (N=153) showed improvements in the ADHD-RS total score by a mean of 8.3 points (SD: 7.74) and in the ADHD-RS inattentive score by a mean of 5.1 points (SD: 4.78). The improvements observed did not meet clinically meaningful improvement, which is estimated as 10-point difference in Total Score based on literature.4 For a comparison of clinical study outcomes between the subject and predicate studies, see Table 2.
Figure 1. Mean TOVA-ACS Score Bar Chart Comparison across Subject and Predicate Studies
Image /page/11/Figure/3 description: This image is a bar graph comparing the mean TOVA-ACS with a 95% confidence interval for three age groups: 18y+, 13-17y, and 8-12y. The data is presented for both the baseline and exit stages. The y-axis represents the mean TOVA-ACS with a 95% confidence interval, ranging from -10 to 10. The sample sizes for each age group at baseline are: Ages 18y+ N=221, Ages 13-17y N=162, and Ages 8-12y N=179, while at exit, the sample sizes are: Ages 18y+ N=153, Ages 13-17y N=146, and Ages 8-12y N=170.
Markers represent individual subject values. Two participants in STARS-ADHD-Adults were enrolled that did not meet inclusions criteria of baseline TOVA-ACS ≤ -1.8 and were reported as protocol violations. TOVA-ACS scores below zero suggest performance similar to individuals with ADHD.5
Study results were based on a modified intent-to-treat (mITT, also known as Efficacy population, is all enrolled subjects with drop outs excluded) population. This population included all enrolled participants with sufficient data at baseline and exit to calculate change scores (N=153) instead of the intent-to-treat (ITT, also known as Safety Population, is all subjects enrolled in the study) population (N=221).
4 Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinational study as a clinicianadministered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi:10.1002/mpr.7
5 TOVA Clinical Manual 2020, p. 32 of 78: https://files.tovatest.com/documentation/9/Clinical%20Manual.pdf
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A sensitivity analysis using multiple imputation (MI) was performed to assess the impact of missing exit data in the ITT population. Change in TOVA-ACS was generally similar in the ITT population after imputation, with a mean [95% CI] of 6.144 [5.037, 7.273] as compared with the mITT population 6.460 [5.349, 7.570]. See Table 3 for a Modified Intent-to-Treat (mlTT) and Intent-to-Treat (ITT) Analysis with Multiple Imputation (MI) of the Primary Efficacy Endpoint - TOVA-ACS Change from Baseline to Exit.
Overall, 11 (5.0%) subjects experienced a treatment-emergent adverse device event (TE-ADE). Reports include 4 (1.8%) nausea, 3 (1.4%) headaches, 2 (0.9%) decreased frustration tolerance, and 1 each (0.5%) of arthritis, dizziness, fatigue, and somnolence. All TE-ADEs were mild or moderate. There were no serious adverse device events. See Table 4 for a comparison of clinical safety outcomes from the subject study with predicate studies.
Akili has conducted and published additional studies that support the lack of a placebo effect on the TOVA67 . Patients and health care providers should consider the totality of the clinical evidence in light of this before using this product.
The clinical performance study demonstrates that EndeavorOTC is safe and effective for its intended use in the indicated patient population.
NOTE: This single arm study did not include a sham control group and it is therefore possible that observed effects were due to bias or placebo effects. Users should consider the totality of the clinical evidence in light of this before using the product.
Some persons with known comorbid psychiatric conditions were excluded from this study and therefore the risk profile for persons with comorbid psychiatric conditions is not fully known.
6 Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
7 Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
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Table 1. Clinical study design description comparison
| | Subject Device
K233496 | Predicate Device
DEN200026 | |
|--------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | STARS-Adult Study
(ages 18+) | STARS Study (ages 8-
12) | Comparison describing differences and a
rationale why it is acceptable |
| Population | Verified ADHD
diagnosis with
impaired attention;
on or off medication | Verified ADHD
diagnosis with
impaired attention;
medication
exclusionary | SIMILAR - the adult study allowed for
medication as long as use was stable for
≥4 weeks prior to study enrollment and
throughout the study. A prior study
demonstrated benefits of intervention on
the pediatric population with ADHD both
on and off medication. |
| Study Design | Single arm, open-
label, adaptive
design | Randomized clinical
trial | DIFFERENT - Presence of attentional
improvement from treatment compared
to those on active control was established
in the STARS study. The adult study
investigated the magnitude of
improvement and safety in the new age
range. |
| | | | The Adult study used an adaptive design
based on the total information as
measured by the standard error of the
primary endpoint which would allow the
trial to be stopped prior to recruitment of
the 325 participants derived from the
sample size calculations. The adaptive
design accounts for the uncertainty
regarding whether the variation in TOVA-
ACS mean change differed between the
adult and pediatric ADHD populations. |
| | | | The safety and effectiveness of the exact
same device was established in an RCT De
Novo in a younger population. The primary
endpoint used in the current study was
identical to the original STARS RCT. Based
on the predicate RCT, the primary
outcome measure TOVA demonstrates
less susceptibility to placebo effect in the |
| | randomized, controlled trial utilized for
the de novo.
Another consideration for the single arm
design is that the TOVA-ACS is less
susceptible to placebo effects when
measuring attentional control processes
within the context of ADHD, as supported
by the predicate RCT and multiple
published studies in the literature. 8,9,10 | | |
| Intervention | EndeavorRx (AKL-
T01) | EndeavorRx (AKL-T01)
EVO: Words (Active
control) | SIMILAR - All use the same active
intervention, minor differences in
software. |
| Treatment
regimen | 25 minutes/day for 5
days/week | 25 minutes per day, 5
days per week | SIMILAR |
| Participant
Duration | Approximately 6
weeks on treatment | Approximately 4
weeks on treatment | DIFFERENT - In Adults, treatment duration
was adjusted to match duration used in
past adult studies using a similar SSME™-
driven product |
| Diagnosis of ADHD | Yes - Diagnosis of
ADHD combined or
inattentive type,
required according to
Diagnostic and
Statistical Manual of
Mental Disorders,
Fifth Edition (DSM-5)
as confirmed by
Mini International
Neuropsychiatric
Interview (MINI) for
Attention - Deficit /
Hyperactivity | Yes - Confirmed ADHD
diagnosis, any
presentation, required
at Screening based on
DSM-V criteria and
established via the
MINI-KID administered
by a
trained clinician | SIMILAR - An age-appropriate version of
the MINI was used in the adult study. |
| | Disorders Studies
(Adult) 7.0.2 | | |
| Sites | Multi-site: 14 sites
across the US (a mix
of institutional sites
and private practice
centers) | Multi-site: 20 sites
across the US (a mix of
institutional sites and
private practice
centers) | SIMILAR |
| Enrollment | 223 enrolled | 348 enrolled | SIMILAR - the larger N in STARS study
takes into account two arms. In Adults,
sample size was determined by power
calculations. |
| Stably on or off
ADHD medications | Stably on or off
stimulant medication
(≥4 weeks) allowed
Stably on or off non-
stimulant medication
(≥4 weeks) allowed | Stimulant medication
use not allowed
Use of non- stimulant
ADHD medication not
allowed | DIFFERENT - Another published study11
demonstrated ADHD improvement
occurred similarly in patients both stably
on and off ADHD medications. This
criterion was adopted into the adult study
design to better simulate real-world user
base
The adult study allowed non-stimulant
medication use as long as stability 4-
weeks before and after study enrollment is
maintained to better represent the
diversity of patients who may use the
device and to generalize to real-world user
base. |
| Stably on or off
nonpharmacologic
al treatments | Stably on or off
nonpharmacological
treatments (≥4
weeks) allowed | Stably on or off
nonpharmacological
treatments (≥4 weeks)
allowed | SIMILAR |
| Absence/Presence
of comorbid
psychiatric
diagnosis and/or
treatments that
may confound | Presence of
comorbid psychiatric
diagnosis and/or
treatments that may
confound study not
allowed | Presence of comorbid
psychiatric
diagnosis and/or
treatments that may
confound study not
allowed | SIMILAR |
| study | | | |
| Absence/Presence
of conditions that
would prevent the
proper use of the
investigational
product | Presence of
conditions that
would prevent the
proper use of the
investigational
product not allowed | Presence of conditions
that would prevent
the proper use of the
investigational
product not allowed | SIMILAR |
| Primary Outcome
Measure | Change in TOVA
attention comparison
score (ACS) from pre-
to post-intervention | Change in TOVA
attention performance
index (API, also known
as TOVA-ACS) from
pre- to post-
intervention | SIMILAR |
| Secondary
Outcome
Measures | Mean changes in:
• ADHD-Rating Scale-
IV (ADHD-RS)
Inattention
Subscale Score
• ADHD-RS Total
Scale Score | Mean changes in:
• ADHD-RS Total Score
• ADHD-RS Inattention
Subscale Score
• ADHD-RS
Hyperactivity
Subscale
• BRIEF Working
Memory percentile
• BRIEF Inhibit
percentile
• Impairment Rating
Scale (IRS)
• Clinical Global
Impression (CGI) | DIFFERENT -The predicate device used the
Impairment Rating Scale (IRS) and the
Clinical Global Impressions Scale (CGI) to
assess functional impairment, but since
the IRS is a parent reported measure and
the CGI was not sensitive to treatment
effects in the predicate study, neither was
used in the subject study, which used the
Adult ADHD Quality of Life (AAQoL) Scale
as a measure of ADHD impairment in
adults.
Both studies had ADHD-RS as secondary
measures. Whereas the STARS study listed
multiple secondary measures, the adult
study focused on ADHD-RS as the
secondary measure, which the predicate
study showed to be sensitive to the AKL-
T01 treatment. |
| Outcome Measure | Clinical Study for
EndeavorOTC
(K233496) | Clinical Study used to
support EndeavorRx
(DEN200026) | Differences |
| | Adults
(ages 18+) | STARS
(ages 8-12) | |
| 1. pre-post change
score on TOVA ACS
(Positive change | 6.46 | 0.93 | Adults show nearly 6 times the
improvement in TOVA-ACS than in
STARS. |
| indicates
improvement) | | | Although the magnitude of benefit
is different between EndeavorOTC
and the predicate device, both
devices show improvement in
TOVA-ACS Score. |
| 2. pre-post change
score on ADHD-RS
Inattention
subscale
(Negative change
indicates
improvement) | -5.1 | -3.6 | Greater mean change than STARS.
Although the magnitude of benefit
is different between EndeavorOTC
and the predicate device, both
devices show improvement in
ADHD-RS Inattentive Scale Score,
which did not reach a clinically
meaningful threshold. Clinically
meaningful improvement based
on literature for the ADHD-RS is
estimated at 10-point difference.12 |
| 3. pre-post change
score on ADHD-RS
Total Score
(Negative change
indicates
improvement) | -8.3 | -6.2 | SIMILAR - Greater or comparable
mean change to STARS. |
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8 Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
9 Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
10 Murray DW, Childress A, Giblin J, Williamson D, Armstrong R, Starr HL. Effects of OROS methylphenidate on academic, behavioral, and cognitive tasks in children 9 to 12 years of age with attention-deficit/hyperactivity disorder. Clin Pediatr (Phila). 2011;50(4):308-320. doi:10.1177/0009922810394832
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11 Kollins, S.H., Childress, A, Heusser, AC and Lutz, J. (2021). Effectiveness of a digital therapeutic as adjunct to treatment with medication in pediatric ADHD. npj Digit. Med. 4, 58. https://doi.org/10.1038/s41746-021-00429-0 AKILI CONFIDENTIAL
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Table 2. Clinical Study Outcome Comparison Table
12 Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinational study as a clinicianadministered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi:10.1002/mpr.7
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Table 3. Modified Intent-to-Treat (mlTT and Intent-to-Treat (ITT) Analysis with Multiple Imputation (MI) of the Primary Efficacy Endpoint – TOVA-ACS Change from Baseline to Exit
| Analysis | Baseline
TOVA-ACS | Exit
TOVA-ACS | Change from
Baseline |
|-------------------------------------------|----------------------|------------------|-------------------------|
| STARS ITT Population | | | |
| n | 179 | 170 | 169 |
| Mean (SD) | -5.11 (0.22) | -4.16 (0.28) | 0.93 (0.24) |
| 95% CI | | | 0.45, 1.40 |
| p-value1 | | | 0.0002 |
| Adult Efficacy Population (mITT) | | | |
| n | 153 | 153 | 153 |
| Mean (SE) | -8.739 (0.6089) | -2.279 (0.3978) | 6.460 (0.5621) |
| 95% CI | | | 5.349, 7.570 |
| p-value1 | | | Substantial equivalence was supported by clinical and non-clinical performance (verification and validation) tests, which complied with the requirements specified in the international and FDA-recognized consensus standards, ISO 14971, IEC 62304, and IEC 82304. The nonclinical testing included software testing, which verified the minor software changes in EndeavorOTC. Clinical testing validated the safety and effectiveness of EndeavorOTC for its intended use in the indicated patient age range of 18 years and older. The clinical trial results showed a significant improvement in the primary effectiveness measure, TOVA, a digitally assessed measure of sustained and selective attention. Results also showed improvements in ADHD symptoms as assessed in key secondary measures, the ADHD-RS inattention scale and ADHD-RS total score, which did not reach clinically meaningful significance estimated at 10-points in literature13. These results were similar to the findings of the prior clinical trial that supported the original clearance of EndeavorRx for 8-12 year-old patients under DEN200026. The clinical testing also showed no new or increased safety risks in the expanded patient population compared to the predicate device.
The results of these tests demonstrate that EndeavorOTC is as safe and effective as its predicate device. Therefore, EndeavorOTC is substantially equivalent.
Benefit-Risk Profile: No serious adverse events were reported. Of the 221 subjects who received AKL-T01 in the adult study supporting EndeavorOTC authorization for ages 18 years and above, 11 (5.0%) subjects experienced 13 treatment-emergent adverse device events (TE-ADE). Reports include 4 (1.8%) nausea, 3 (1.4%) headaches, 2 (0.9%) decreased frustration tolerance, and 1 each (0.5%) of arthritis, dizziness, fatigue, and somnolence. Three TE-ADEs (somnolence, fatigue, and arthritis) were considered unanticipated, and 3 TE-ADEs (1 occurrence of headache and 2 occurrences of nausea) resulted in study treatment discontinuation. All TE-ADEs were either mild or moderate in severity, and all were considered related to the study treatment.
43 Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinationadministered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi:10.1002/mpr.7
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There were no serious adverse device events. All adverse events were resolved by the end of treatment.
EndeavorOTC showed a general improvement in attention associated with ADHD. The totality of the evidence demonstrated clinical benefit in attention, as measured by the TOVA in the adult population (18+ years) with ADHD with a demonstrated attention issue. Improvements in ADHD inattentive symptoms were comparable or greater than the improvements in ADHD inattentive symptoms seen in the pediatric population from the predicate studies. As noted, the risks associated with EndeavorOTC are minimal.
For EndeavorOTC, the AE rates were low, in mild-moderate severity range. There were no SAEs, and all TE-ADEs were resolved by the end of the clinical trial. Given the favorable safety profile, even small benefits in inattentive ADHD symptoms would justify use of the product.
The benefits of the EndeavorOTC have been found to outweigh the individual risks. After evaluating all benefits, risks and applicable considerations, it has been determined that the overall residual risk of the EndeavorOTC is acceptable, and the product is considered safe for use by the intended user within the intended use environment.